Use of substituted N,N-disubstituted non-fused heterocyclo amino compounds for inhibiting cholesteryl ester transfer protein activity

ABSTRACT

The invention relates to use of substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamine compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-I) and compounds, compositions and methods for treating atherosclerosis and other coronary artery diseases. Preferred tertiary-heteroalkylamine compounds are substituted N,N-disubstituted non-fused heterocyclo amines. A preferred specific N,N-disubstituted non-fused heterocyclo amine is the compound:

RELATED APPLICATIONS

This is a divisional of pending U.S. patent application Ser. No. 09/405,524, filed Sep. 23, 1999.

FIELD OF THE INVENTION

This invention is in the field of treating cardiovascular disease, and specifically relates to compounds, compositions and methods for treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamine compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-I.

BACKGROUND OF THE INVENTION

Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (1996)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.

Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/LDL ratios. Inhibition of CETP by the subject compounds is shown to effectively modify plasma HDL/LDL ratios, and to check the progress and/or formation of these diseases.

CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy, Medicinal Res. Revs., 13, 139-59 (1993); Sitori, Pharmac. Ther., 67,443-47 (1995)). This exact phenomenon was first demonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta 795, 743-480 (1984)), Morton et al. (J. Lipid Res. 35, 836-847 (1994)) and Tollefson et al. (Am. J. Physiol., 255, (Endocrinol. Metab. 18, E894-E902 (1988))) describe proteins from human plasma that inhibit CETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity. Cho et al. (Biochim. Biophys. Acta 1391, 133-144 (1998)) describe a peptide from hog plasma that inhibits human CETP. Bonin et al. (J. Peptide Res., 51, 216-225 (1998)) disclose a decapeptide inhibitor of CETP. A depsipeptide fungal metabolite is disclosed as a CETP inhibitor by Hedge et al. in Bioorg. Med. Chem. Lett., 8, 1277-80 (1998).

There have been several reports of non-peptidic compounds that act as CETP inhibitors. Barrett et al. (J. Am. Chem. Soc., 188, 7863-63 (1996)) and Kuo et al. (J. Am. Chem. Soc., 117, 10629-34 (1995)) describe cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett., 5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Japanese Patent Application No. 10287662-A describes polycyclic, non-amine containing, polyhydroxylic natural compounds possessing CETP inhibition properties. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 (1996)) describe other cysteine modification reagents as CETP inhibitors. Xia et al. describe 1,3,5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett., 6, 919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994)) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor. Oomura et al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETP inhibitors in Japanese Patent Application No. 10287662. In WO Patent Application No. 09914204, Sikorski describes 1,2,4-triazolylthiols useful as chlolesteryl ester transfer protein inhibitors.

Some substituted heteroalkylamine compounds are known. In European Patent Application No. 796846, Schmidt et al. describe 2-aryl-substituted pyridines as cholesteryl ester transfer protein inhibitors useful as cardiovascular agents. One substitutent at C3 of the pyridine ring can be an hydroxyalkyl group. In European Patent Application No. 801060, Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1-hydroxy-1-amines. These are reported to be β3-adrenergic receptor agonists useful for treating diabetes and other disorders. In Great Britain Patent Application No. 2305665, Fisher et al. disclose 3-agonist secondary amino alcohol substituted pyridine derivatives useful for treating several disorders including cholesterol levels and artherosclerotic diseases. In European Patent Application No. 818448, Schmidt et al. describe tetrahydroquinoline derivatives as chlolesteryl ester transfer protein inhibitors. European Patent Application No. 818197, Schmek et al. describe pyridines with fused heterocycles as cholesteryl ester transfer protein inhibitors. Brandes et al. in German Patent Application No. 19627430 describe bicyclic condensed pyridine derivatives as cholesteryl ester transfer protein inhibitors. In WO Patent Application No. 09839299, Muller-Gliemann et al. describe quinoline derivatives as cholesteryl ester transfer protein inhibitors. U.S. Pat. No. 2,700,686, issued to Dickey and Towne, describes N-(2-haloalkyl-2-hydroxyethyl)amines in which the amine is further substituted with either 1 to 2 aliphatic groups or one aromatic group and one aliphatic group. U.S. Pat. No. 2,700,686 further describes a process to prepare the N-(2-haloalkyl-2-hydroxyethyl)amines by reacting halogenated-1,2-epoxyalkanes with the corresponding aliphatic amines and N-alkylanilines and their use as dye intermediates.

SUMMARY OF THE INVENTION

The present invention provides compounds that can be used to inhibit cholesteryl ester transfer protein (CETP) activity and that have the general structure:

In another aspect , the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.

In another aspect, this invention relates to methods of using these inhibitors as therapeutic agents in humans to inhibit cholesteryl ester transfer protein (CETP) activity, thereby decreasing the concentrations of low density lipoprotein (LDL) and raising the level of high density lipoprotein (HDL), resulting in a therapeutically beneficial plasma lipid profile. The compounds and methods of this invention can also be used to treat dyslipidemia (hypoalphalipoproteinemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinemia), peripheral vascular disease, hypercholesterolaemia, atherosclerosis, coronary artery disease and other CETP-mediated disorders. The compounds can also be used in prophylactic treatment of subjects who are at risk of developing such disorders. The compounds can be used to lower the risk of atherosclerosis. The compounds of this invention would be also useful in prevention of cerebral vascular accident (CVA) or stroke. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals such as primates, rabbits, pigs, horses, and the like.

DESCRIPTION OF THE INVENTION

The present invention relates to a class of compounds comprising substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamines which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula V-H (also referred to herein as generic substituted polycyclic aryl and heteroaryl tertiary omegaheteroalkylamines):

or a pharmaceutically acceptable salt thereof, wherein;

m is an integer selected from 0 through 5;

n is an integer selected from 0 through 5;

m plus n is an integer selected from 0 through 6;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH), N(alkyl), and N(alkoxy):

R₁₆ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of an aromatic substituent selected from the group consisting of R₄, R₈, R₉, R₁₃, R₁₄, and R₁₅ to form a heterocyclyl ring having from 5 through 10 contiguous members with the provisos that said spacer moiety is other than a covalent single bond when R₂ is alkyl and there is no R₁₆ wherein X is H or F;

D₁, D₂, J₁, J₂ and K₁ are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁, D₂, J₁, J₂ and K₁ can be N;

D₃, D₄, J₃, J₄ and K₂ are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D₃, D₄, J₃, J₄ and K₂ can be a covalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, no more than one of D₃, D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

R₂ is independently selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

R₂ and R₃ can be taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;

R₂ and R₁₄ can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear spacer moiety having from 1 through 5 contiguous atoms to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that said spacer group is other than —N═;

R₂ and R₁₅ can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear spacer moiety having from 1 through 5 contiguous atoms to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that said spacer group is other than —N═;

R₂ and R₁₉ can be taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a linear moiety having from 1 through 5 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkylenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;

R₂ and R₄, R₂ and R₈, R₂ and R₉, and R₂ and R₁₃ can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear spacer moiety wherein said linear spacer moiety is selected to form a heterocyclyl ring having from 5 through 10 contiguous members;

R₃ is selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

R₃ and R₁₄ can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear moiety having from 1 through 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;

R₃ and R₁₅ can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear moiety having from 1 through 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;

R₃ and R₁₉ can be taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a linear moiety having a chain length of 1 to 5 atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkylenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;

R₃ and R₄, R₃ and R₈, R₃ and R₉, and R₃ and R₁₃ can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear spacer moiety wherein said linear spacer moiety is selected to form a heterocyclyl ring having from 5 through 10 contiguous members;

Y is selected from a group consisting of a covalent single bond, (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 4 and (CH(R₁₄))_(g)—W—(CH(R₁₄))_(p) wherein g and p are integers independently selected from 0 through 2;

R₁₄ is independently selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R₉ and R₁₃ to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R₄ and R₈ to form a heterocyclyl having from 5 through 8 contiguous members with the proviso that, when Y is a covalent bond, an R₁₄ substituent is not attached to Y;

R₁₄ and R₁₅ can be taken together to form a spacer selected from a moiety having a chain length of 2 to 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;

R₁₄ and R₁₉ can be taken together to form a spacer selected from a moiety having a chain length of 2 to 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;

R₁₄ and R₁₄, when bonded to the different atoms, can be taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;

R₁₄ and R₁₄, when bonded to the same atom can be taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;

W is selected from the group consisting of O, C(O), C(S), C(O)N(R₁₄), C(S)N(R₁₄), (R₁₄)NC(O), (R₁₄NC(S), S, S(O), S(O)₂, S(O)₂N(R₁₄), (R₁₄)NS(O)₂, and N(R₁₄) with the proviso that R₁₄ is selected from other than halo and cyano;

Z is independently selected from a group consisting of a covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 4, (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 2 with the proviso that, when Z is a covalent single bond, an R₁₅ substituent is not attached to Z;

R₁₅ is independently selected, when Z is (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 4, from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R₄ and R₈ to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R₉ and R₁₃ to form a heterocyclyl having from 5 through 8 contiguous members;

R₁₅ and R₁₉ can be taken together to form a spacer selected from the group consisting of a covalent single bond and a linear moiety having a chain length of 2 to 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;

R₁₅ and R₁₅, when bonded to the different atoms, can be taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;

R₁₅ and R₁₅, when bonded to the same atom can be taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;

R₁₅ is independently selected, when Z is (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 2, from the group consisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a linear moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R₄ and R₈ to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a linear moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R₉ and R₁₃ to form a heterocyclyl ring having from 5 through 8 contiguous members;

R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R ₁₁, R₁₂, and R₁₃ are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoal koxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the proviso that there are one to five non-hydrido ring substituents R₄, R₅, R₆, R₇, and R₈ present, that there are one to five non-hydrido ring substituents R₉, R₁₀, R₁₁, R₁₂, and R₁₃ present, and R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈, can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time;

R₄ and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ can be independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R₄ and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ can be used at the same time;

R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ can be independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a C8 to C13 heterocyclyl ring having from 8 through 13 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ can be used at the same time;

R₁₉ is selected from the group consisting of hydrido, hydroxyalkyl, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkanoyl, heteroarylthio, aralkylthio, aroyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, and a spacer group selected from the group consisting of a covalent single bond and a linear moiety having a chain length of 2 to 5 atoms connected to a point of bonding selected from the group consisting of R₄, R₈, R₉, and R₁₃ to form a heterocyclyl ring having from 5 through 8 contiguous members.

In another embodiment, the compounds correspond to Formula V-H wherein m is an integer selected from 0 through 5; n is an integer selected from 0 through 5; the sum of m plus n is an integer selected from 0 through 6; D₁, D₂, D₃, D₄, J₁, J₂, J₃, J₄, K₁, and K₂ are each a carbon atom; and a terminal carbon atom of the CH(R₃) moiety is directly connected by a covalent single bond to the nitrogen when m=0. Compounds of Formula V-H wherein m is an integer selected from 0 through 5, n is an integer selected from 0 through 5, the sum of m plus n is an integer selected from 0 through 6, and D₁, D₂, D₃, D₄, J₁, J₂, J₃, J₄, K₁, and K₂ are each a carbon atom, have the CH(R₃) moiety directly connected by a covalent single bond to the nitrogen when m=0 and correspond to Formula V (also referred to herein as generic phenyl tertiary omegaheteroalkylarmines):

or a pharmaceutically acceptable salt thereof, wherein;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₉, X, Y, and Z are as defined for the compounds of Formula V-H;

D₁, D₂, D₃, D₄, J₁, J₂, J₃, J₄, K₁, and K₂ are each carbon;

R₁₆ and R₄, R₁₆ and R₈, R₁₆ and R₉, R₁₆ and R₁₃, R₂ and R₃, R₉ and R₁₄, R₁₃ and R₁₄, R₄ and R₁₄, R₈ and R₁₄, R₁₄ and R₁₄, R₄ and R₁₅, R₈ and R₁₅, R₉ and R₁₅, R₁₃ and R₁₅, R₁₅ and R₁₅ R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, R₁₂ and R₁₃, R₄ and R₉, R₄ and R₁₃, R₈ and R₉, R₈ and R₁₃, R₁₆ and R₁₄, R₁₆ and R₁₅, R₂ and R₁₄, R₂ and R₁₅, R₂ and R₁₉, R₂ and R₄, R₂ and R₈, R₂ and R₉, R₂ and R₁₃, R₃ and R₁₄, R₃ and R₁₅, R₃ and R₁₉, R₃ and R₄, R₃ and R₈, R₃ and R₉, R₃ and R₁₃, R₁₄ and R₁₉, R₁₄ and R₁₅, R₁₅ and R₁₉, R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ spacer pairs are as defined for the compounds of Formula V-H.

In another embodiment, the compounds correspond to Formula V-H wherein m is an integer selected from 0 through 5; n is an integer selected from 0 through 5; the sum of m plus n is an integer selected from 0 through 6; and a terminal carbon atom of the CH(R₃) moiety is directly connected by a covalent single bond to the nitrogen when m=0. Compounds of Formula V-H wherein wherein m is the integer zero, and n is an integer selected from 0 through 5, have the CH(R₃) moiety directly connected by a covalent single bond to the nitrogen when m=0 and correspond to Formula VII-H (also referred to herein as generic substituted polycyclic heteroaryl tertiary 2-heteroalkylamines):

or a pharmaceutically acceptable salt thereof, wherein;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, D₁, D₂, D₃, D₄, J₁, J₂, J₃, J₄, K₁, K₂, X, Y, and Z are as defined for the compounds of Formula V-H;

R₁₆ and R₄, R₁₆ and R₈, R₁₆ and R₉, R₁₆ and R₁₃, R₂ and R₃, R₉ and R₁₄, R₁₃ and R₁₄, R₄ and R₁₄, R₈ and R₁₄, R₁₄ and R₁₄, R₄ and R₁₅, R₈ and R₁₅, R₉ and R₁₅, R₁₃ and R₁₅, R₁₅ and R₁₅, R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, R₁₂ and R₁₃, R₄ and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ spacer pairs are as defined for the compounds of Formula V-H;

R₁₉ and spacer pairs R₁₆ and R₁₄, R₁₆ and R₁₅, R₂ and R₁₄, R₂ and R₁₅, R₂ and R₁₉, R₂ and R₄, R₂ and R₈, R₂ and R₉, R₂ and R₁₃, R₃ and R₁₄, R₃ and R₁₅, R₃ and R₁₉, R₃ and R₄, R₃ and R₈, R₃ and R₉, R₃ and R₁₃, R₁₄ and R₁₉, R₁₄ and R₁₅, R₁₅ and R₁₉, R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ are not present.

In another embodiment of compounds of Formula VII-H,

D₁, D₂, J₁, J₂ and K₁ are each carbon with the proviso that at least one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consisting of O, S, and N, wherein D₃, D₄, J₃, J₄ and K₂ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of D₃, D₄, J₃, J₄ and K₂ can be a covalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, no more than one of D₃, D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

D₁, D₂, J₁, J₂ and K₁ can be selected from the group consisting of C, O, S, N and covalent bond with the provisos that D₃, D₄, J₃, J₄ and K₂ are each carbon and at least one of D₁, D₂, J₁, J₂ and K₁ is selected from the group consisting of O, S, and N wherein, when D₁, D₂, J₁, J₂ and K₁ are selected from the group consisting of C, O, S, covalent bond, and N, no more than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁, D₂, J₁, J₂ and K₁ can be N;

n is an integer selected from 1 through 4;

X is oxy;

R₁₆ is selected from the group consisting of hydrido, acyl, aroyl, and trialkylsilyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂ is selected from the group consisting of hydrido, hydroxy, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Y is selected from the group consisting of covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 2;

W is oxy;

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁ and R₁₂ are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈ can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In a more specific embodiment of compounds of Formula VII-H,

D₁, D₂, J ₁, J₂ and K₁ are each carbon;

D₃, D₄, J₃, J₄ and K₂ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at least one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consisting of O, S, and N, wherein no more than one of D₃, D₄, J₃, J₄ and K₂ can be a covalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, no more than one of D₃, D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

n is an integer selected from 1 through 3:

X is oxy;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₁₆ is selected from the group consisting of acetyl, benzoyl, dimethyl tert -butylsilyl, hydrido, and trimethylsilyl;

R₂ is selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.

In a more specific embodiment of compounds of Formula VII-H,

D₃, D₄, J₃, J₄ and K₂ are each carbon;

D₁, D₂, J₁, J₂ and K₁ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at least one of D₁, D₂, J₁, J₂ and K₁ is selected from the group consisting of O, S, and N, wherein no more than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁, D₂, J₁, J₂ and K₁ can be N;

n is an integer selected from 1 through 3;

X is oxy;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₁₆ is selected from the group consisting of acetyl, benzoyl, dimethyl tert -butylsilyl, hydrido, and trimethylsilyl;

R₂ is selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.

In a preferred embodiment of compounds of Formula VII-H, the compounds correspond to the Formula VII (also referred to herein as generic phenyl tertiary 2-heteroalkylamines):

or a pharmacuetically acceptable salt thereof, wherein;

n is an integer selected from 0 through 4;

X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH), N(alkyl), and N(alkoxy);

R₁₆ is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of any aromatic substituent selected from the group consisting of R₄, R₈, R₉, and R₁₃ to form a heterocyclyl ring having from 5 through 10 contiguous members with the proviso that said linear spacer moiety is other than covalent single bond when R₂ is alkyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂ is selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocyanoalkyl, and dicyanoalkyl, carboalkoxycyanoalkyl;

R₃ is selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, aroyl, heteroaroyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl;

Y is selected from the group consisting of covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 2;

W is selected from the group consisting of O, C(O), C(S), C(O)N(R₁₄), C(S)N(R₁₄), (R₁₄)NC(O), (R₁₄)NC(S), S, S(O), S(O)₂, S(O)₂N(R₁₄), (R₁₄)NS(O)₂, and N(R₁₄) with the proviso that R₁₄ is other than cyano;

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈, can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In a preferred embodiment of compounds of Formula VII, compounds have the Formula VII-2:

wherein;

n is an integer selected from 1 through 4;

R₁₆ is selected from the group consisting of hydrido, acyl, aroyl, and trialkylsilyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂ is selected from the group consisting of hydrido, hydroxy, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Y is selected from the group consisting of covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 2;

W is oxy;

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂ and R₁₂ and R₁₃ spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈ can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In a more preferred embodiment of compounds of Formula VII-2,

n is an integer selected from 1 through 2;

R₁ is selected from the group consisting of haloalkyl and haloalkoxyalkyl;

R₁₆ is hydrido;

R₂ is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;

R₃ is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;

Y is selected from the group consisting of a covalent single bond and alkylene;

Z is selected from the group consisting of a covalent single bond and alkylene;

R₁₄ is selected from the group consisting of hydrido, alkyl, and haloalkyl;

R₁₅ is selected from the group consisting of hydrido, alkyl, and haloalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and halo;

R₅, R₆, R₇, R₁₀, R₁₁ and R₁₂ are independently selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.

In an even more preferred embodiment of compounds of Formula VII-2,

n is the integer 1;

R₁₆ is hydrido;

R₁ is haloalkyl;

R₂ is selected from the group consisting of hydrido, alkyl, haloalkyl, aryl, and haloalkoxy;

R₃ is selected from the group consisting of hydrido, alkyl, and haloalkyl;

Y is alkylene;

Z is covalent single bond;

R₁₄ is hydrido;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and halo;

R₅, R₆, R₇, R₁₀, R₁₁ and R₁₂ are independently selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, and heteroaryloxyalkyl.

In an embodiment of compounds of Formula VII-2,

n is an integer selected from 1 to 3;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₁₆ is selected from the group consisting of acetyl, benzoyl, dimethyl tert-butylsilyl, hydrido, and trimethylsilyl;

R₂ is selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.

In a preferred embodiment of compounds of Formula VII-2,

n is the integer 1;

R₁₆ is hydrido;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₂ is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₃ is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, ethyl, vinyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

In a even more preferred embodiment of compounds of Formula VII-2,

n is the integer 1;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₁₆ is hydrido;

R₂ is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethyl, trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₃ is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;

In a most preferred embodiment of compounds of Formula VII-2,

n is the integer 1;

R₁ is selected from the group consisting of trifluoromethyl and pentafluoroethyl;

R₁₆ is hydrido;

R₂ is selected from the group consisting of hydrido, phenyl, and trifluoromethyl;

R₃ is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl;

In another embodiment of compounds of Formula VII, compounds have the Formula Cyclo-VII:

wherein:

R₁₆ is taken together with R₄, R₈, R₉ or R₁₃ to form a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms to form a heterocyclyl ring having from 5 through 10 contiguous members with the proviso that said linear spacer moiety is other than covalent single bond when R₂ is alkyl;

n is an integer selected from 1 through 3;

X is selected from the group consisting of O, S, NH, N(alkyl), and N(alkoxy);

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂ is selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocyanoalkyl, and dicyanoalkyl, carboalkoxycyanoalkyl;

R₃ is selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, aroyl, heteroaroyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl;

Y is selected from the group consisting of covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 2;

W is selected from the group consisting of O, C(O), S, S(O), and S(O)_(2;)

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ can be independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁ and R₁₂ are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl;

R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R₅ and R₆, R₆ and R₇, and R₇ and R₈, can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₀, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In an embodiment of compounds of Formula Cyclo-VII,

n is the integer 1;

X is selected from the group consisting of O, NH, and S;

R₁₆ is taken together with R₄, R₈, R₉ or R₁₃ to form a spacer selected from the group consisting of a covalent single bond, CH₂, CH(CH₃), CF₂, C(O), C(S), and SO₂;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₂ is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, vinyl, trifluoromethyl, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₃ is selected from the group consisting of hydrido, methyl, ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl.

In another embodiment of compounds of Formula Cyclo-VII, compounds have the formula:

n is the integer 1;

X is oxy;

R₁₆ and R₄ are taken together to form a covalent single bond;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₂ is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, vinyl, trifluoromethyl, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₃ is selected from the group consisting of hydrido, methyl, ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl.

In another embodiment of compounds of Formula VII, compounds have the Formula VII-3:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl and haloalkenyloxyalkyl;

R₂ is hydroxyalkyl;

Y is selected from the group consisting of covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 2;

W is oxy;

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryldioxylene with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈ can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In an embodiment of compounds of Formula VII-3,

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, and pentafluorophenoxymethyl;

R₂ is hydroxymethyl, 1-hydroxyethyl, and 1,2-dihydroxyethyl.

In another embodiment of compounds of Formula VII, compounds have the Formula VII-4:

wherein;

X is oxy;

R₁ is selected from the group consisting of haloalkyl and haloalkoxyalkyl;

R₁₆ is hydrido;

R₂ and R₃ are taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;

Y is selected from the group consisting of a covalent single bond and alkylene;

Z is selected from the group consisting of a covalent single bond and alkylene;

R₁₄ is selected from the group consisting of hydrido, alkyl, and haloalkyl;

R₁₅ is selected from the group consisting of hydrido, alkyl, and haloalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and halo;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.

In an embodiment of compounds of Formula VII-4,

X is oxy;

R₁₆ is hydrido;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₂ and R₃ spacer pair is selected from the group consisting of —CH₂SCH₂—, —CH₂OCH₂—, —CH₂CH(R₁₇)—, —CH═C(R₁₇)—, —CH₂S(O)₂CH₂—, —CH₂CH₂CH(R₁₇)—, —CH₂CH(R₁₇)CH₂—, —CH₂CH═C(R₁₇)—, —CH(R₁₇)CH═CH—, —CH₂C(R₁₇)═CH—, —CH(R₁₇)C(O)N(R₁₇)—, —C(O)N(R₁₇)CH(R₁₇)—, —CH(R₁₇)C(O)NHCH₂—, —CH₂C(O)NHCH(R₁₇)—, —CH(R₁₇)CH(R₁₇)C(O)NH—, —C(O)NHCH(R₁₇)CH(R₁₇)—, —CH₂CH(R₁₇)CH₂CH₂—, —CH(R₁₇)CH₂CH₂CH₂—, —CH₂CH═CHCH₂—, —CH═CHCH₂CH₂—, —CH═CHCH═CH—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂—, —(CH₂)₂O—, —(CH₂CHR₁₇)O—, —(CF₂)₂O—, —SCH₂CH₂—, —S(O)CH₂CH₂—, —CH₂S(O)CH₂—, —CH₂S(O)CH₂CH₂—, —S(O)₂CH₂—, —CH₂N(R₁₇)O—, —CH₂CH₂C(O)—, —CH₂C(O)NR₁₇—, and —CH₂NR₁₇CH₂— wherein R₁₇ is selected from the group consisting of H, CH₃, OCH₃, CF₃, CH₂CH₃, F, Cl, CH₂OH, and OH.

In an embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII4, and Cyclo-VII,

Y is selected from the group consisting of a covalent single bond, methylene, 2-fluoroethylidene, ethylidene, 2,2-difluoroethylidene, and 2,2,2-trifluoroethylidene;

Z is group selected from the group consisting of covalent single bond, oxy, methyleneoxy, methylene, ethylene, ethylidene, 2-fluoroethylidene, 2,2-difluoroethylidene, and 2,2,2-trifluoroethylidene;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and fluoro;

R₅ and R₁₀ are independently selected from the group consisting of acetoxy, 3-acetamidophenoxy, 3-acetylphenoxy, 4-acetylphenylsulfonyl, amino, 4-acetylphenylthio, acetylthio, 3-aminobenzyloxy, 4-aminobenzyloxy, 4-aminophenoxy, 3-aminophenyl, benzoyl, benzoylamido, benzoylmethoxy, benzyl, N-benzylamidocarbonyl, benzylamino, 3-benzylimidazol-4-ylmethoxy, N-benzyl-N-methylamidocarbonyl, benzyloxy, 4-benzyloxybenzyloxy, 4-benzylphenoxy, 4-benzylpiperidinyl, bromo, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, bromomethyl, 4-bromo-2-nitrophenoxy, 2-bromobenzyloxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-bromothiophen-3-ylthio, butoxy, 4-butoxyphenoxy, N-butylylcarboxamido, N-butyl-N-methylcarboxamido, N-butylethoxycarbonylphenylamino, 4-butylphenoxy, carboxy, carboxamidomethoxy, 3-carboxybenzyloxy, 4-carboxybenzyloxy, 4-carboxyphenyl, 5-carboxypyrid-3-yloxy, chloro, 3-chlorobenzyl, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chloro-2-hydroxypropoxy, 4-chloro-3-methylphenoxy, 4-chloro-3-methylbenzyl, 2-chloro-4-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chlorofluorophenoxy, 4-chloro-3-fluorophenoxy, 4chloro-2-fluorophenoxy, 3-chloro-4-fluorophenylsulfonylamido, 4-chlorophenyl, 3-chlorophenylamino, 4-chlorophenylamino, 5-chlorophenylthiophen-3-ylmethoxy, 5-chloropyrid-3-yloxy, 4-chlorothiophen-2-ylmethylthio, cyano, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 4-(2-cyano-2-ethoxycarbonylacetyl)phenylamino, N-(2-cyanoethyl)-4-methylphenylamino, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, 4-cyanophenyl, 3-cyanophenylamino, 4-cyanophenylamino, 3-cyanopropoxy, cyclobutoxy, cyclobutyl, cyclohexylamidocarbonyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, N-cyclopentylamidocarbonyl, cyclopentylcarbonyl, 4-cyclopentylphenxoy, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 3,5-dichlorobenzyloxy, 3,5-dichloromethylphenoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 3,5-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichloro-4-methoxyphenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-dichlorophenyl, 3,4-difluorophenoxy, 2,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorobenzyloxy, 2,6-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,4-difluorobenzyloxy, difluoromethoxy, 2,5-difluorophenoxy, 3,5-difluorophenylamino, 3,5-dimethoxyphenoxy, dimethylamino, N,N-dimethylcarboxamido, 2-(N,N-dimethylamino)ethoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,5-dimethyl-4-(N,N-dimethylamino)phenyl, 3,4-dimethoxyphenylamino, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 1,1-dimethylhydroxymethyl, 3,3-dimethyl-2-oxobutoxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, ethoxycarbonyl, 3-ethoxycarbonylphenylamino, 4-ethoxycarbonylphenylamino, 1-ethoxycarbonylbutoxy, 4-ethoxyphenoxy, ethyl, 4,4-ethylenedioxypiperidinyl, N-ethyl-N-methylcarboxamido, 3-ethylphenoxy, 4-ethylaminophenoxy, 4-ethylbenzyloxy, 3-ethyl-5-methylphenoxy, N-ethyl-3-methylphenylamino, N-ethylmethoxyphenylamino, fluoro, 4-fluorobenzylamino, 4-fluoro-3-methylbenzyl, 2-fluoro-3-methylbenzyloxy, 4-fluoro-3-methylphenyl, 4-fluorobenzoyl, 4-fluoro-3-methylbenzoyl, 3-fluorobenzyloxy, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 4-fluoro-2-tifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 5-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamidocarbonylamido, 4-fluorophenylamino, 4-fluorobenzoylamido, 4-fluorobenzylamidocarbonyl, 4-fluoro-2-trifluoromethylphenoxy, 2-fluoro-4-chloromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, N-(2,2,3,3,4,4,4-heptafluorobutyl)amidocarbonyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, hydrazinocarbonyl, hydrido, hydroxy, 2-hydroxyethoxy, 1-hydroxyisobutyl, 3-hydroxy-2,2-dimethylpropoxy, hydroxymethyl, 3-hydroxymethylphenoxy, 4-hydroxyphenoxy, 3-hydroxypropoxy, 2-hydroxy-3,3,3-trifluoropropoxy, 4-imidazol-1-yl-phenoxy, indol-5-yloxy, iodo, 3-iodobenzyloxy, isobutylamino, isobutoxy, N-isobutoxycarbonylamido, isobutyl, isobutyryl, isobutyrylamido, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, isopropylamidocarbonyl, isopropylarnidocarbonylamido, 4-isopropylbenzyloxy, N-isopropyl-N-methylamino, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, isopropylsulfonyl, isopropylsulfonylamido, isoquinolin-3-yloxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, methoxy, 3-methoxybenzoylamido, 3-methoxybenzyl, methoxycarbonyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylbenzyloxy, 4-methoxycarbonylbenzyloxy, 2-methoxyethoxy, 3-methoxycarbonylmethoxy, 3-methoxycarbonylprop-2-enyloxy, methoxymethyl, N-methoxy-N-methylcarboxamido, 3-methoxyphenoxy, 4-methoxyphenoxy, 4-methoxy-3-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methoxyphenylamidocarbonylamido, 4-methoxyphenylthio, methyl, N-methyl-4-methoxyphenylamino, 4-methylbenzyl, 3-methylbutyl, 3-methylphenoxy, 4-methylsulfonylphenyl, 3-methyl-4-methylthiophenoxy, 3-methylbenzyloxy, 4-methylbenzyloxy, 2-methyl-3-nitrophenoxy, 2-methyl-5-nitrophenoxy, 4-methylphenoxy, 4-methylphenyl, N-methyl-N-phenylamidocarbonyl, N-methyl-N-propylcarboxamido, 4-(5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl)phenylamino, 3-methylphenylsulfonylamido, 4-methylpiperazin-1-ylcarbonyl, 1-methylpropoxy, 3-methylbut-2-enyloxy, 2-methylpyrid-6-yl, 3-methylpyrid-2-yl, 2-methylpyrid-3-yloxy, 2-methylpyrid-5-yloxy, N-methylpyrrol-2-yl, 4-methylsulfonylphenylsulfonyl, 4-methylsulfonylphenylthio, 4-methylthiophenoxy, 4-methylthiophenyl, 4-methylthiobenzyl, morpholin-4-ylcarbonyl, 2-naphthyloxy, N-neopentylamidocarbonyl, nitro, 3-nitrobenzyl, 3-nitrobenzyloxy, 4-nitrobenzyloxy, 2-nitrophenoxy, 3-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylsulfonyl, 3-nitrophenylsulfonylamido, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-oxobutoxy, 5-oxohexoxy, N-oxypyrid-3-ylmethylsulfonyl, 2,3,4,5,6-pentafluorobenzyloxy, pentafluoroethyl, pentafluoroethylthio, 4-(2,3,4,5,6-pentafluorophenyl)-2,3,5,6-tetrafluorophenoxy, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, 3-phenoxybenzyloxy, phenyl, phenylamidocarbonylamido, 1-(N-phenylcarboxamido)ethoxy, phenylamino, 4-phenylbenzyloxy, 1-phenylethoxy, phenylhydroxymethyl, 3-phenylphenoxy, 4-phenylphenoxy, phenylsulfonyl, phenylsulfonylamido, 2-phenylsulfonylethoxy, phenylthio, 1-piperidinyl, piperidin-4-ylcarbonyl, piperidin-4-ylsulfonyl, piperidin-4-ylthio, hexahydropyran-4-yloxy, 4-propanoyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propylphenylamino, 4-propoxyphenoxy, pyrid-2-yl, pyrid-3-yl, pyrid-3-ylcarboxamido, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, pyrid-2-yloxy, pyrid-3-yloxy, pyrid-2-ylmethylthio, pyrid-4-ylthio, pyrimid-2-yl, pyrimid-2-yloxy, pyrimid-5-yloxy, pyrrolin-1-ylcarbonyl, 2-(pyrrolidin-1-yl)ethoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert-butoxy, N-tert-butylamidocarbonyl, 4-tert -butylbenzyl, 4-tert-butylbenzyloxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 4-tert-butylphenyl, tetrazol-5-yl, 3-(1,1,2,2-tetrafluoroethoxy)benzylamino, 1,1,2,2-tetrafluoroethoxy, 2,3,5,6-tetrafluoromethoxybenzyloxy, 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyloxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiol, 4-thiophenoxy, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,4,6-trifluorobenzyloxy, N-(4,4,4-trifluorobutyl)methoxyphenylamino, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, N-(2,2,2-trifluoroethyl)amidocarbonyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxybenzylamidocarbonyl, 3-trifluoromethoxybenzylamidocarbonylhydrazinocarbonyl, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenylamino, trifluoromethyl, 3-trifluoromethylbenzylamine, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 3,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3,5-bis-trifluoromethylphenyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenylamidocarbonylamido, 4-trifluoromethylphenylamino, 3-trifluoromethylphenylsulfonylamido, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3,4,5-trimethoxyphenylamino, 3-trifluoromethylpyrid-2-yl, 3-trifluoromethylpyrid-2-yloxy, 5-trifluoromethylpyrid-2-yloxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting of acetoxy, benzyloxy, bromo, butoxy, butoxycarbonyl, chloro, 4-chlorophenyl, 3,4-dichlorophenoxy, cyano, 2-cyanophenyl, difluoromethoxy, ethoxy, fluoro, hydrido, hydroxy, methoxy, methoxycarbonyl, methyl, methylsulfonyl, morpholin-4-yl, nitro, octyl, phenoxy, phenyl, phenylethenyl, phenylethynyl, propoxy, thiophen-2-yl, trifluoromethyl, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethoxy;

R₇ and R₁₂ are independently selected from the group consisting of benzyloxy, hydrido, fluoro, hydroxy, methoxy, and trifluoromethyl;

R₅ and R₆ can be taken together to form a spacer group selected from the group consisting of benzylidene, 5-bromobenzylidene, ethylene-1,2-dioxy, tetrafluoroethylene-1,2-dioxy, 1,4-butadienyl, methylene-1,1-dioxy, phenoxylidene, and propylene-1,3-dioxy;

R₆ and R₇ can be taken together to form a spacer group selected from the group consisting of benzylidene, 5-bromobenzylidene, ethylene-1,2-dioxy, tetrafluoroethylene-1,2-dioxy, 1,4-butadienyl, methylene-1,1-dioxy, phenoxylidene, and propylene-1,3-dioxy;

R₁₀ and R₁₁ can be taken together to form a spacer group selected from the group consisting of benzylidene, ethylene-1,2-dioxy, methylene-1,1-dioxy, phthaloyl, and tetrafluoroethylene-1,2-dioxy;

R₁₁ and R₁₂ can be taken together to form a spacer group selected from the group consisting of benzylidene, ethylene-1,2-dioxy, methylene-1,1-dioxy, phthaloyl, and tetrafluoroethylene-1,2-dioxy;

R₁₂ and R₁₃ can be the spacer group 1,4-butadienyl.

In a preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII,

Y is selected from the group consisting of methylene, ethylene, and ethylidene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and fluoro;

R₅ and R₁₀ are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloromethylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoromethylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluorotrifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;

R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.

In an even more preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII,

Y is methylene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and fluoro;

R₅ and R₁₀ are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;

R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.

In a most preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII4, and Cyclo-VII,

Y is methylene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and fluoro;

R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy;

R₁₀ is selected from the group consisting of cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl, 1,1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting of fluoro and hydrido;

R₇ and R₁₂ are independently selected from the group consisting of hydrido and fluoro.

DEFINITIONS

The use of generic terms in the description of the compounds are herein defined for clarity.

Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol “C” represents a carbon atom. The symbol “O” represents an oxygen atom. The symbol “N” represents a nitrogen atom. The symbol “P” represents a phosphorus atom. The symbol “S” represents a sulfur atom. The symbol “H” represents a hydrogen atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., Cl represents chlorine, Se represents selenium, etc.).

As utilized herein, the term “alkyl”, either alone or within other terms such as “haloalkyl” and “alkylthio”, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.

The term “alkenyl” refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

The term “hydrido” denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a “hydroxyl” radical, one hydrido radical may be attached to a carbon atom to form a “methine” radical (═CH—), or two hydrido radicals may be attached to a carbon atom to form a “methylene” (—CH₂—) radical.

The term “carbon” radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.

The term “cyano” radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.

The term “hydroxyalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.

The term “alkanoyl” embraces radicals wherein one or more of the termninal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.

The term “alkylene” radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, ethylidene, methylethylene, and isopropylidene.

The term “alkenylene” radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH₂═C), 1,2-vinylidene (—CH═CH—), and 1,4-butadienyl (—CH═CH—CH═CH—).

The term “halo” means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are “lower haloalkyl” radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term “hydroxyhaloalkyl” embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of “hydroxyhaloalkyl” radicals include hexafluorohydoxypropyl.

The term “haloalkylene radical” denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are “lower haloalkylene” radicals having one to about six carbon atoms. Examples of “haloalkylene” radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.

The term “haloalkenyl” denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term “alkoxyalkyl” also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” and “haloalkoxyalkyl” radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.

The terms “alkenyloxy” and “alkenyloxyalkyl” embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term “alkenyloxyalkyl” also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are “lower alkenyloxy” radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The “alkenyloxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkenyloxy” radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy.

The term “haloalkoxyalkyl” also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term “haloalkenyloxy” also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term “haloalkenyloxyalkyl” also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.

The term “alkylenedioxy” radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of “alkylenedioxy” radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term “haloalkylenedioxy” radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of “haloalkylenedioxy” radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.

The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term “fused” means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term “fused” is equivalent to the term “condensed”. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The term “perhaloaryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.

The term “heterocyclyl” embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed “heteroaryl” radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclyl” group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heterocyclic radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO₂—. “Alkylsulfonyl”, embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. “Alkylsulfonylalkyl”, embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. “Haloalkylsulfonyl”, embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. “Haloalkylsulfonylalkyl”, embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term “aminosulfonyl” denotes an amino radical attached to a sulfonyl radical.

The term “sulfinyl”, whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals —S(O)—. “Alkylsulfinyl”, embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. “Alkylsulfinylalkyl”, embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. “Haloalkylsulfinyl”, embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. “Haloalkylsulfinylalkyl”, embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.

The term “heteroaralkyl” embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term “perhaloaralkyl” embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.

The term “aralkylsulfinyl”, embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. “Aralkylsulfinylalkyl”, embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “aralkylsulfonyl”, embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. “Aralkylsulfonylalkyl”, embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “cycloalkyl” embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term “cycloalkenyl” embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term “halocycloalkyl” embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are “lower halocycloalkyl” radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term “halocycloalkenyl” embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.

The term “cycloalkoxy” embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy. The term “cycloalkoxyalkyl” also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The “cycloalkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “halocycloalkoxy” and “halocycloalkoxyalkyl” radicals.

The term “cycloalkylalkoxy” embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.

The termn “cycloalkenyloxy” embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term “cycloalkenyloxyalkyl” also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The “cycloalkenyloxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “halocycloalkenyloxy” and “halocycloalkenyloxyalkyl” radicals.

The term “cycloalkylenedioxy” radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of “alkylenedioxy” radicals include 1,2-dioxycyclohexylene.

The term “cycloalkylsulfinyl”, embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above. “Cycloalkylsulfinylalkyl”, embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term “Cycloalkylsulfonyl”, embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. “Cycloalkylsulfonylalkyl”, embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “cycloalkylalkanoyl” embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane..

The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having one to six carbon atoms. An example of “lower alkylthio” is methylthio (CH₃—S—). The “alkylthio” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkylthio” radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.

The term “alkyl aryl amino” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.

The terms alkylamino denotes “monoalkylanrino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.

The terms arylamino denotes “monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical. Examples of such radicals include N-phenylamino and N-naphthylamino.

The term “aralkylarino”, embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes “monoaralkylamino” and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes “monoaralkyl monoalkylamino” containing one aralkyl radical and one alkyl radical attached to an amino radical.

The term “arylsulfinyl” embraces radicals containing an aryl radical, as defined above, attached to a divalent S(═O) atom. The term “arylsulfinylalkyl” denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.

The term “arylsulfonyl”, embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. “arylsulfonylalkyl”, embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term “heteroarylsulfinyl” embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(═O) atom. The term “heteroarylsulfinylalkyl” denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term “Heteroarylsulfonyl”, embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. “Heteroarylsulfonylalkyl”, embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “aryloxy” embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 4-tert -butylphenoxy, 3-pentafluoroethylphenoxy, and 3-(1,1,2,2-tetrafluoroethoxy)phenoxy.

The term “aroyl” embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.

The term “aralkanoyl” embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are “lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and 2-phenylethoxy.

The term “aryloxyalkyl” embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.

The term “haloaryloxyalkyl” embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.

The term “heteroaroyl” embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.

The term “heteroaralkanoyl” embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.

The term “heteroaralkoxy” embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are “lower heteroaralkoxy” radicals having heteroaryl radicals attached to lower alkoxy radical as described above.

The term “haloheteroaryloxyalkyl” embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.

The term “heteroarylamino” embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.

The term “heteroarylaminoalkyl” embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino.

The term “heteroaryloxy” embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy.

The term “heteroaryloxyalkyl” embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.

The term “arylthio” embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.

The term “arylthioalkyl” embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.

The term “alkylthioalkyl” embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term “alkoxyalkyl” embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.

The term “carbonyl” denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term “carboxy” embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term “carboxamide” embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term “carboxamidoalkyl” embraces carboxamide radicals, as defined above, attached to an alkyl group. The term “carboxyalkyl” embraces a carboxy radical, as defined above, attached to an alkyl group. The term “carboalkoxy” embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term “carboaralkoxy” embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term “monocarboalkoxyalkyl” embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term “dicarboalkoxyalkyl” embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term “monocyanoalkyl” embraces one cyano radical, as defined above, attached to an alkyl group. The term “dicyanoalkylene” embraces two cyano radicals, as defined above, attached to an alkyl group. The term “carboalkoxycyanoalkyl” embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group.

The term “acyl”, alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of “acyl” are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term “haloalkanoyl” embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl. The term “diacyl”, alone or in combination, means having two or more carbonyl or thionocarbonyl groups bonded to a radical selected from, for example, alkylene, alkenylene, alkynylene, haloalkylene, alkoxyalkylene, aryl, heterocyclyl, heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl. Examples of “diacyl” are phthaloyl, malonyl, succinyl, adipoyl, and the like.

The term “benzylidenyl” radical denotes substituted and unsubstituted benzyl groups having attachment points for two covalent bonds. One attachment point is through the methylene of the benzyl group with the other attachment point through an ortho carbon of the phenyl ring. The methylene group is designated for attached to the lowest numbered position. Examples include the base compound benzylidene of structure:

The term “phenoxylidenyl” radical denotes substituted and unsubstituted phenoxy groups having attachment points for two covalent bonds. One attachment point is through the oxy of the phenoxy group with the other attachment point through an ortho carbon of the phenyl ring. The oxy group is designated for attached to the lowest numbered position. Examples include the base compound phenoxylidene of structure:

The term “phosphono” embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term “dialkoxyphosphono” denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term “diaralkoxyphosphono” denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term “dialkoxyphosphonoalkyl” denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term “diaralkoxyphosphonoalkyl” denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.

Said “alkyl”, “alkenyl”, “alkynyl”, “alkanoyl”, “alkylene”, “alkenylene”, “benzylidenyl”, “phenoxylidenyl”, “hydroxyalkyl”, “haloalkyl”, “haloalkylene”, “haloalkenyl”, “alkoxy”, “alkenyloxy”, “alkenyloxyalkyl”, “alkoxyalkyl”, “aryl”, “perhaloaryl”, “haloalkoxy”, “haloalkoxyalkyl”, “haloalkenyloxy”, “haloalkenyloxyalkyl”, “alkylenedioxy”, “haloalkylenedioxy”, “heterocyclyl”, “heteroaryl”, “hydroxyhaloalkyl”, “alkylsulfonyl”, “haloalkylsulfonyl”, “alkylsulfonylalkyl”, “haloalkylsulfonylalkyl”, “alkylsulfinyl”, “alkylsulfinylalkyl”, “haloalkylsulfinylalkyl”, “aralkyl”, “heteroaralkyl”, “perhaloaralkyl”, “aralkylsulfonyl”, “aralkylsulfonylalkyl”, “aralkylsulfinyl”, “aralkylsulfinylalkyl”, “cycloalkyl”, “cycloalkylalkanoyl”, “cycloalkylalkyl”, “cycloalkenyl”, “halocycloalkyl”, “halocycloalkenyl”, “cycloalkylsulfinyl”, “cycloalkylsulfinylalkyl”, “cycloalkylsulfonyl”,“cycloalkylsulfonylalkyl”, “cycloalkoxy”, “cycloalkoxyalkyl”, “cycloalkylalkoxy”,“cycloalkenyloxy”, “cycloalkenyloxyalkyl”, “cycloalkylenedioxy”, “halocycloalkoxy”, “halocycloalkoxyalkyl”, “halocycloalkenyloxy”, “halocycloalkenyloxyalkyl”, “alkylthio”, “haloalkylthio”, “alkylsulfinyl”, “amino”, “oxy”, “thio”, “alkylarino”, “arylamino”, “aralkylamino”, “arylsulfinyl”, “arylsulfinylalkyl”, “arylsulfonyl”, “arylsulfonylalkyl”, “heteroarylsulfinyl”, “heteroarylsulfinylalkyl”, “heteroarylsulfonyl”, “heteroarylsulfonylalkyl”, “heteroarylamiino”, “heteroarylaminoalkyl”, “heteroaryloxy”, “heteroaryloxylalkyl”, “aryloxy”, “aroyl”, “aralkanoyl”, “aralkoxy”, “aryloxyalkyl”, “haloaryloxyalkyl”, “heteroaroyl”, “heteroaralkanoyl”, “heteroaralkoxy”, “heteroaralkoxyalkyl”, “arylthio”, “arylthioalkyl”, “alkoxyalkyl”, “acyl” and “diacyl” groups defined above may optionally have 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

The term “spacer” can include a covalent bond and a linear moiety having a backbone of 1 to 7 continous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from ═C(H)—, ═C(R₁₇)—, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —N(R₁₇)—, —N═, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—, ═C(O₁₇)—, and —C(O)— wherein R₁₇ is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, —O—, —O—CH₂—, —S—CH₂—, —CH₂CH₂—, ethenyl, —CH═CH(OH)—, —OCH₂O—, —O(CH₂)₂O—, —NHCH₂—, —OCH(R₁₇)O—, —O(CH₂CHR₁₇)O—, —OCF₂O—, —O(CF₂)₂O—, —S—, —S(O)—, —S(O)₂—, —N(H)—, —N(H)O—, —N(R₁₇)O—, —N(R₁₇)—, —C(O)—, —C(O)NH—, —C(O)NR₁₇—, —N═, —OCH₂—, —SCH₂—, S(O)CH₂—, —CH₂C(O)—, —CH(OH)—,═C(OH)—, —CH(OR₁₇)—, ═C(OR₁₇)—, S(O)₂CH₂—, and —NR₁₇CH₂— and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.

The terms “cis” and “trans” denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond (“cis”) or on opposite sides of the double bond (“trans”).

Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or “E” and “Z” geometric forms.

Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.

Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the “keto” form and in part or principally as one or more “enol” forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms.

Some of the compounds described herein may contain one or more amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the “keto” form and in part or principally as one or more “enol” forms of each amide group present. Compounds of the present invention having amidic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms. Said amide carbonyl groups may be both oxo (C═O) and thiono (C═S) in type.

Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the “imine” form and in part or principally as one or more “enamine” forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both “imine” and “enamine” tautomeric forms.

The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes are as follows: “AA” represents amino acids, “BINAP” represents 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, “Boc” represents tert-butyloxycarbonyl, “BOP” represents benzotriazol-1-yl-oxy-tris-(dimethylamino), “bu” represents butyl, “dba” represents dibenzylideneacetone, “DCC” represents 1,3-dicyclohexylcarbodiimide, “DIBAH” represents diisobutylaluminum hydride, “DIPEA” represents diisopropylethylamine, “DMF” represents dimethylformamide, “DMSO” represents dimethylsulfoxide, “Fmoc” represents 9-fluorenylmethoxycarbonyl, “LDA” represents lithium diisopropylamide, “PHTH” represents a phthaloyl group, “pnZ” represents 4-nitrobenzyloxycarbonyl, “PTC” represents a phase transfer catalyst, “p-TsOH” represents paratoluenesulfonic acid, “TBAF” represents tetrabutylammonium fluoride, “TBTU” represents 2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, “TEA” represents triethylamine, “TFA” represents trifluoroacetic acid, “THF” represents tetrahydrofuran, “TMS” represents trimethylsilyl, and “Z” represents benzyloxycarbonyl.

Pharmaceutical Utility and Composition

The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.

The present invention also comprises a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula V-H:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₉, X, Y, and Z are as defined above for the compounds of Formula V-H;

or a pharmaceutically-acceptable salt thereof.

As a further embodiment, compounds of the present invention of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, or a pharmaceutically-acceptable salt thereof as defined above and further including those, wherein R₁₆ is a covalent single bond linked to a point of bonding of R₄ or R₈ when R₂ is alkyl, R₂ and R₁₄ are taken together to form a —N═ spacer group, and R₂ and R₁₅ are taken together to form a —N═ spacer group, comprise a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, of the present invention or a pharmaceutically-acceptable salt thereof.

Compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII including those, wherein R₁₆ is a covalent single bond linked to a point of bonding of R₄ or R₈ when R₂ is alkyl, R₂ and R₁₄ are taken together to form a —N═ spacer group, and R₂ and R₁₅ are taken together to form a —N═ spacer group, are capable of inhibiting activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both, or a procedure to study the mechanism of action of the cholesteryl ester transfer protein (CETP) to enable the design of better inhibitors. The compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII would be also useful in prevention of cerebral vascular accident (CVA) or stroke.

Also included in the family of compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII are the pharmaceutically-acceptable salts thereof. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula V-H may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula V-H include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII by reacting, for example, the appropriate acid or base with the compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII.

Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formula V-H in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.

The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.

The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

All mentioned references are incorporated by reference as if here written.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

General Synthetic Procedures

The compounds of the present invention can be synthesized, for example, according to the following procedures of Schemes 1 through 59 below, wherein the substituents are as defined for Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII above except where further noted.

Synthetic Schemes 1 and 2 shows the preparation of compounds of formula XIII (“Generic Secondary Amines”) which are intermediates in the preparation of the compounds of the present invention corresponding to Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”), Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”), and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) wherein A and Q are independently aryl and heteroaryl. Schemes 1 and 2, taken together, prepare tertiary oxyalkylamine compounds of the present invention by addition of a halogenated, oxygen containing precursor to a secondary amine to introduce an oxy containing alkyl group wherein the two groups making up the secondary amine both are made up of aromatic groups or both groups contain aromatic rings wherein said aromatic rings maybe 0 to 2 aryl rings and 0 to 2 heteroaryl rings.

The “Generic Imine” corresponding to Formula XII can be prepared through dehydration techniques generally known in the art and the preferred technique depending on the nature of “Generic Amine-1” of Formula X by reacting it with the “Generic Carbonyl Compound” of Formula XI. For example, when Z is a covalent bond, methylene, methine substituted with another subsitutent, ethylene, or another subsituent as defined in Formula V-H, the two reactants (X and XI) react by refluxing them in an aprotic solvent, such as hexane, toluene, cyclohexane, benzene, and the like, using a Dean-Stark type trap to remove water. After about 2-8 hours or until the removal of water is complete, the aprotic solvent is removed in vacuo to yield the “Generic Imine” of Formula XII. Alternately, when Z is an oxygen, the “Generic Imine” is an oxime derivative. Oxime type “Generic Imine” compounds are readily prepared from the corresponding O-substituted hydroxylamine and the appropriate aldehyde or ketone type “Generic Carbonyl Compound”. Suitable procedures are described by Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons and by Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference. Alternately, when Z is a nitrogen, the “Generic Imine” is a hydrazone derivative. Hydrazone type “Generic Imine” compounds are readily prepared from the corresponding hydrazine and the appropriate aldehyde or ketone type “Generic Carbonyl Compound”. Suitable procedures for forming the hydrazone imines are also described by Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and by Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference.

Scheme 1 shows the preparation of “Generic Imine” compounds in which the amine functionality is bonded to Z; Z is bonded to A; and Y is bonded to Q. One of skill in the art will recognize that A and Q as defined can be structurally interchanged to prepare “Generic Imine” compounds with similar, identical or different structures.

The “Generic Secondary Amines” of Formula XIII can be prepared from the corresponding “Generic Imine” of Formula XII in several ways.

For example, in one synthetic scheme (Reduction Method-1), which is preferred when Z is a nitrogen, the “Generic Imine” hydrazone of Formula XII is partially or completely dissolved in lower alkanols such as ethanol or like solvent containing sufficient organic acid such as acetic acid or mineral acid such as HCl or sulfuric acid to neutralize the hydrazone as described in WO Patent Application No.9738973, Swiss Patent CH 441366 and U.S. Pat. Nos. 3,359,316 and 3,334,017, which are incorporated herein by reference. The resulting mixture is then hydrogenated at 0-100° C., more preferrably 20-50° C., and most preferrably between 20-30° C. and pressures of 10-200 psi hydrogen or more preferrably between 50-70 psi hydrogen in the presence of a noble metal catalyst such as PtO₂. The mixture is cooled, and a base such as sodium carbonate or sodium hydroxide added until the solution is neutral to just alkaline (pH 6-8).

Isolation of the desired product can be accomplished, for example, by removing the ethanol, adding water, and extracting the aqueous-organic mixture twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous magnesium sulfate, and concentrated in vacuo to yield the “Generic Secondary Amines” hydrazine of Formula XIII. If needed the “Generic Secondary Amines” hydrazine can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.

In another synthetic scheme (Reduction Method-2), which is preferrred when Z is a single bond or carbon, the “Generic Imine” of Formula XII is slurried in a lower alcohol such as ethanol, methanol or like solvent at 0-10° C. and solid sodium borohydride is added in batches over 5-10 minutes at 0-10° C. with stirring. The reaction mixture is stirred below 10° C. for 30-90 minutes and then is warmed gradually to 15-30° C. After about 1-10 hours, the mixture is cooled and acid is added until the aqueous layer was just acidic (pH 5-7).

Isolation of the desired product can be accomplished, for example, by extracting the aqueous layer twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous MgSO4, and concentrated in vacuo to yield the “Generic Secondary Amines” amine, aniline, or amine of Formula XIII. If needed the “Generic Secondary Amines” amine, aniline, or amine derivative can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.

In yet another synthetic scheme (Reduction Method-3), which is preferrred when Z is an oxygen, the “Generic Imine” oxime of Formula XII is slurried in a lower alcohol solvent such methanol or like solvent at 0-10° C. and acidified to a pH less than 4. Solid sodium cyanoborohydride is added in batches over 30-90 minutes at 0-20° C. with stirring and addition of a suitable organic or mineral acid to keep the pH at or below 4. The reaction mixture is stirred and warmed gradually to about 20-25° C. After about 1-10 hours, the mixture is cooled and base added until the mixture was just slightly alkaline.

Isolation of the desired product can be accomplished, for example, by removing the methanol or other low boiling solvent in vacuo. The residue is slurried with water and aqueous-organic mixture is extracted twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous MgSO₄, and concentrated in vacuo to yield the “Generic Secondary Amines” hydroxylamine of Formula XIII. If needed the “Generic Secondary Amines” hydroxylamine can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.

The “Generic Secondary Amines” of Formula XIII can also be prepared, according to Scheme 1 by two alkylation procedures based on the nucleophilic substitution of bromides by amines. In one procedure, “Generic Amine-1” of Formula X is reacted with “Generic Bromide-1” of Formula XXI. In another alkylation procedure, “Generic Amine-2” of Formula XXII is reacted together with “Generic Bromide-2” of Formula XXIII.

In one synthetic alkylation scheme (Alkylation Method-1), a “Generic Amine-1” of Formula X is reacted with a “Generic Bromide-2” of Formula XXIII as described in Vogel's Textbook of Practical Organic Chemistry, Fifth Edition, 1989, pages 902 to 905 and references cited therein all of which are incorporated herein by reference. In this procedure, the “Generic Amine-1” is placed in a reaction vessel equipped with a reflux condenser with the capability to either cool or heat the vessel as dictated by the reaction. A suitable “Generic Amine-1” will be selected from primary amine and primary aromatic amine classes of compounds. Cooling may be needed and used should the reaction prove strongly exothermic. Heating may be needed and used to drive the reaction to completion. A suitable solvent may also be used to dissolve the “Generic Amine-1”. Suitable solvents are hydrocarbons such as toluene, hexane, xylene, and cyclohexane, ethers, amides such as dimethylformamide, esters such as ethyl acetate, ketones such as acetone, and nitriles such as acetonitrile or mixtures of two or more of these solvents. A suitable base is also added to the reaction vessel. Suitable bases include cesium carbonate, calcium carbonate, sodium carbonate and sodium bicarbonate. The base will normally be added in at least a stoichmetric quantity compared to the “Generic Amine-1” so as to neutralize liberated acid as it forms.

The “Generic Bromide-1” of Formula XXI is then added to the reaction vessel in portions so as to minimize the rate of heat evolution and minimize the concentration of the “Generic Bromide-1”. The “Generic Bromide-1” will be selected from primary and secondary organic alkyl and substituted alkyl halide compounds. The halide will preferrably be a bromide although iodides and chlorides may also be generally used. One of skill in the art will also be able to readily select and utilize organic alkyl and substituted alkyl compounds containing readily displaceable primary and secondary groups such as tosylates, mesylates, triflates, and the like. Alternately, the halides can be generally prepared from the corresponding alcohols by reaction with, for example, concentrated hydrohalic acids such as HBr or by reaction with phosphorus trihalides such as PBr₃ as described in Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference. The appropriate alcohols can be converted to tosylates, mesylates, and triflates using procedures described below.

Addition of the “Generic Bromide-1” is carried out over a period of a few minutes to several hours at temperatures between 0 and 150° C. Preferrably, the addition will take 30-120 minutes at a temperature of 0 to 50° C. The reaction can be stirred until completion. Completion can be monitored, for example, spectroscopically using nuclear magnetic resonance or chromatographically using thin layer, liquid, or gas chromatographic procedures. If the reaction does not proceed to completion, the reactants may be heated until completion is obtained and verified.

Isolation of the desired product can be accomplished, for example, when a water immiscible solvent was used for the reaction, by adding water to the finished reaction. Additional base such as sodium carbonate can be added to ensure the reaction is basic (pH of 9 to 11). The organic layer containing the “Generic Secondary Amine” is washed with saturated brine, dried with a drying agent such as anhydrous MgSO₄, and concentrated in vacuo to yield the “Generic Secondary Amine” amine, aniline, or amine of Formula XIII. If needed the “Generic Secondary Amine” amine, aniline, or amine derivative can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.

In a second synthetic alkylation scheme (Alkylation Method-2), a “Generic Amine-2” of Formula XXII is reacted with a “Generic Bromide-2” of Formula XXIII in a method employing pallladium catalyzed carbon-nitrogen bond formation. Suitable procedures for this conversion are described in Wagaw and Buchwald, J. Org. Chem.(1996), 61, 7240-7241, Wolfe, Wagaw and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, and Wolfe and Buchwald, Tetrahedron Letters (1997), 38(36), 6359-6362 and references cited therein all of which are incorporated herein by reference. The preferred “Generic Bromide-2” of Formula XXIII are generally aryl bromides, aryl triflates, and heteroaryl bromides.

The “Generic Amine-1” and “Generic Amine-2” amines, hydroxylamines, and hydrazines, the “Generic Carbonyl Compound” aldehydes, ketones, hydrazones, and oximes, and “Generic Bromide-1” and “Generic Bromide-2” halides, tosylates, mesylates, triflates, and precursor alcohols required to prepare the “Generic Secondary Amine” compounds are available from commercial sources, can be prepared by one skilled in the art from published procedures, and/or can be obtained using specific procedures shown in Schemes 42, 43, and 44. Commercial sources include but are not limited to Aldrich Chemical, TCI-America, Lancaster-Synthesis, Oakwood Products, Acros Organics, and Maybridge Chemical. Disclosed procedures for “Generic Amine” amines, hydroxylamines, and hydrazines include Sheradsky and Nov, J. Chem. Soc., Perkin Trans.1 (1980), (12), 2781-6; Marcoux, Doye, and Buchwald, J. Am. Chem. Soc. (1997), 119, 1053-9; Sternbach and Jamison, Tetrahedron Lett. (1981), 22(35), 3331-4; U.S. Pat. No. 5,306,718; EP No. 314435; WO No. 9001874; WO No. 9002113; JP No. 05320117; WO No. 9738973; Swiss Patent No. CH 441366; U.S. Pat. Nos. 3,359,316 and 3,334,017; and references cited therein which are incorporated herein by reference. Representative specific “Generic Secondary Amine” of Formula XIII compounds useful for the preparation of compounds of the present invention are listed in Tables 3, 4, and 5.

As summarized in the general Scheme 1 and specific descriptions above, Schemes 3, 4, 9, and 10 illustrate the principles of Scheme 1 for the preparation of specifically substituted “Secondary Heteroaryl Amines” (XIIIA-H) having 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups and “Secondary Phenyl Amines” (XIII-A) having two aryl groups.

Synthetic Scheme 2 shows the preparation of the class of compounds of the present invention corresponding to Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”), Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”), and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) wherein A and Q are independently aryl and heteroaryl.

Derivatives of “Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines” and “Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”, wherein A and Q are independently aryl and heteroaryl, in which the hetero atom (—O—) is attached to an alkyl group removed from the amine by three or more carbons are readily prepared by anion chemistry using Method B of Scheme 2. The anion of “Generic Secondary Amine” amines, hydroxylamines, and hydrazines of Formula XIII are readily formed by dissolving the specific amine, hydroxylamine, or hydrazine in an aprotic solvent, such as tetrahydrofuran, toluene, ether, dimethylformamide, and dimethylformamide, under anhydrous conditions. The solution is cooled to a temperature between −78 and 0° C., preferrably between −78 and −60° C. and the anion formed by the addition of at least one equivalent of a strong, aprotic, non-nucleophillic base such as NaH or n-butyllithium under an inert atmosphere for each acidic group present. Maintaining the temperature between −78 and 0° C., preferrably between −78 and −60° C., with suitable cooling, an appropriate alkyl

TABLE 3 Structure of “Secondary Phenyl Amine” Reagents.

Secondary Phenyl Amine (XIIIA) Reagent Number R₄ R₅ R₆ R₇ R₉ R₁₀ R₁₁ Y R₁₄  1N H phenoxy H H H OCF₂CF₂H H CH H  2N H OCF₃ H H H OCF₂CF₂H H CH H  3N F H H F H OCF₂CF₂H H CH H  4N H F H H H OCF₂CF₂H H CH H  5N H phenoxy H H H OCF₃ H CH H  6N H OCF₃ H H H OCF₃ H CH H  7N H H phenyl H H OCF₃ H CH H  8N H phenyl H H H OCF₃ H CH H  9N H H H H H OCF₃ H CH H 10N H Br H H H OCF₃ H CH H 11N H CF₃ F H H CF₃ H CH H 12N H CH₃ H H H CF₃ H CH H 13N H CF₃ H H H CF₃ H CH H 14N H CH₃ H H H OCF₃ H CH H 15N H F F H H OCF₃ H CH H 16N H Br H H H CF₃ H CH H 17N H CF₃ F H H OCF₃ H CH H 18N H F H H H OCF₃ H CH H 19N H Cl H H H OCF₃ H CH H 20N H F H H H CF₃ H CH H 21N H F F H H CF₃ H CH H 22N H Cl H H H CF₃ H CH H 23N H F H H H phenoxy H CH H 24N H CF₃ Cl H H CH₃ H CH H 25N H CF₃ F H H CH₃ H CH H 26N H H H H H CF₃ H CH H 27N F F H H H CF₃ H CH H 28N H H OCH₃ H H CF₃ H CH H 29N H F F H H CH₃ H CH H 30N H OCH₃ H H H CH₃ H CH H 31N H H CH₃ H H H H CH H 32N H Cl H H H H H CH H 33N H F H H H F H CH H 34N H H OCH₃ H H CH₃ H CH H 35N H H H H H H H CH H 36N H H CH₃ H H CH₃ H CH H 37N H H Cl H H H H CH H 38N H F H H H 3-CF₃—phenoxy H CH H 39N H F H H H 4-CH₃O—phenoxy H CH H 40N H F H H H 4-Cl—phenoxy H CH H 41N H F H H H H H CH H 42N H F H H H CH₃ H CH H 43N H F H F H CH₃ H CH H 44N F F H H H CH₃ H CH H 45N H Cl H H H CH₃ H CH H 46N H CH₃ H H H CH₃ H CH H 48N H H CH₃ H H CF₃ H CH H 51N H H CH₃ H H F H CH H 52N H CF₃ H H H F H CH H 53N H CF₃ H H H CH₃ H CH H 54N H OCH₃ H H H CF₃ H CH H 56N H H CH₃ H H CF₃ H CH H 57N H phenoxy H H H H OCF₃ CH H 58N H H H H H H OCF₃ CH H 59N H OCF₃ H H H H OCF₃ CH H 60N H CF₃ F H H H CF₃ CH H 61N H H OCH₃ H H H CF₃ CH H 62N H CH₃ H H H H CF₃ CH H 63N H Cl H H H H CF₃ CH H 64N H CF₃ H H H H OCF₃ CH H 65N H F H H H H OCF₃ CH H 66N H F H F H H OCF₃ CH H 67N H Br H H H H OCF₃ CH H 68N H Cl H H H H OCF₃ CH H 69N H F F H H H OCF₃ CH H 70N H F H H H H phenyl CH H 71N H CH₃ H H H H OCF₃ CH H 72N H F F H H H CF₃ CH H 73N H Cl H H H H CH₃ CH H 74N H OCH₃ H H H H CH₃ CH H 75N H F H H H H CH₃ CH H 76N F F H H H H OCF₃ CH H 78N H H OCH₃ H H H CH₃ CH H 79N H H CH₃ H H H CH₃ CH H 80N H CH₃ H H H H CH₃ CH H 82N H F F H H H CH₃ CH H 83N H F H F H H CH₃ CH H 84N F F H H H H CH₃ CH H 85N F CF₃ H H H H CH₃ CH H 86N H H CH₃ H H H CF₃ CH H 88N H CF₃ H H H H CH₃ CH H 90N H H CF₃ H H H CH₃ CH H 92N H CF₃ F H H H CH₃ CH H

TABLE 4 Structure of “Secondary Phenyl Amine” Reagents (Z is covalent bond; there is no R₁₅ substituent; R₄ and R₁₃ equal H) Secondary Phenyl Amine (XIII-A)

Spacer Rgnt. Bond No. R₅ R₆ R₇ R₈ Y R₁₄ R₉ R₁₀ R₁₁ R₁₂ Spacer Points  93N Br H H CH H H H OCF₃ —O— R₈ + R₉  94N OCF₃ H H CH H H H OCF₃ — R₈ + R₉  95N Br H H C H OCF₃ H H ═CH— R₈ + R₁₄  96N OH OH H H CH H H C₆H₅O H H none none  97N C₆H₅O H H H CH H H OH OH H none none  98N 3-pyridyl H H H CH H H CF₃ H H none none  99N SO₂N H H H CH H H OCF₃ H H none none (CH₃)₂ 100N SO₂CH₃ H H H CH H H OCF₃ H H none none 101N C₆H₅O H H H CH H H C₆H₅O H H none none 102N CF₃O H H H CH H H C₆H₅O H H none none 103N C₆H₅ H H H CH H H C₆H₅O H H none none 104N H C₆H₅ H H CH H H C₆H₅O H H none none 105N C₆H₅O H H H CH H H 4-Cl—C₆H₄O H H none none 106N CF₃O H H H CH H H 4-Cl—C₆H₄O H H none none 107N C₆H₅O H H H CH H H 3,4-Cl—C₆H₃O H H none none 108N CF₃O H H H CH H H 3,4-Cl—C₆H₃O H H none none 109N CF₃O H H H CH H H 3,5-Cl—C₆H₃O H H none none 110N CF₃O H H H CH H H 3-CH₃O— H H none none C₆H₄O 111N CF₃O H H H CH H H H 3-CH₃O— H none none C₆H₄O 112N CF₃O H H H CH H H 3-CF₃—C₆H₄O H H none none 113N CF₃O H H H CH H H C₆H₅—CH₂O H H none none 114N CF₃O H H H CH H H C₆H₅—CH₂O CH₃O H none none 115N CF₃O H H H CH H H C₆H₅—CH₂O C₆H₅— H none none CH₂O 116N CF₃O H H H CH H H ethoxy H H none none 117N CF₃O H H H CH H H CH₃CO₂ H H none none 118N CF₃O H H H CH H H HOCH₂— H H none none CH₂O 119N CF₃O H H H CH H H

H H none none 120N CF₃O H H H CH H H R₁₀ + R₁₁ = OCH₂O H none none 121N CF₃O H H H CH H H R₁₀ + R₁₁ = OCH₂CH₂O H none none 122N CF₃O H H H CH H H CH₃O CH₃O H none none 123N CF₃O H H H CH H H ethoxy CH₃O H none none 124N CF₃O H H H CH H H ethoxy ethoxy H none none 125N CF₃O H H H CH H H CH₃CO₂ CH₃CO₂ H none none 126N CF₃O H H H CH H H CH₃O CH₃CO₂ H none none 127N CF₃O H H H CH H H n-butoxy H H none none 128N CF₃O H H H CH H H CH₃O H H none none 129N CF₃O H H H CH H H H CH₃O H none none 130N CH₃O H H H CH H H CH₃O H H none none 131N CH₃O H H H CH H H H CF₃O H none none 132N CF₃O H H H CH H H H ethoxy H none none 133N CF₃O H H H CH H H H n-propoxy H none none 134N C₆H₅—CH₂O H H H CH H H CF₃O H H none none 135N C₆H₅—CH₂O H H H CH H H C₆H₅O H H none none 136N ethoxy H H H CH H H CF₃O H H none none 137N R₅ + R₆ = OCH₂O H H CH H H CF₃O H H none none 138N R₅ + R₆ = OCH₂O H H CH H H C₆H₅O H H none none 139N R₅ + R₆ = OCH₂CH₂O H H CH H H CF₃O H H none none 140N CH₃O CH₃O H H CH H H CF₃O H H none none 141N R₅ + R₆ = OCH₂CH₂CH₂O H H CH H H CF₃O H H none none 142N cyclo CH₃O H H CH H H CF₃O H H none none pentoxy 143N H C₆H₅O H H CH H H CF₃O H H none none 144N CH₃O CH₃O CH₃O H CH H H CF₃O H H none none 145N H CF₃O H H CH H H CF₃O H H none none 146N H Benzyl H H CH H H CF₃O H H none none 147N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCH₂CH₂O H none none 148N H CF₃O H H CH H H CF₃ H H none none 149N C₆H₅O H H H CH H H CF₃ H H none none 150N C₆H₅ H H H CH H H CF₃ H H none none 151N H C₆H₅ H H CH H H CF₃ H H none none 152N CN H H H CH H H CF₃ H H none none 153N H OCF₃ H H CH H H CF₃ H H none none 154N OCF₃ H H H CH H H H CF₃ H none none 155N C₆H₅O H H H CH H H H CF₃ H none none 156N C₆H₅ H H H CH H H H CF₃ H none none 157N H C₆H₅ H H CH H H H CF₃ H none none 158N CN H H H CH H H H CF₃ H none none 159N OCF₃ H H H CH H H H CF₃ H none none 160N CF₃ H H H CH H H H C₆H₅ H none none 161N CF₃ H H H CH H H 3-CF₃— H H none none C₆H₅O 162N CF₃ H H H CH H H C₆H₅O H H none none 163N CF₃ H H H CH H H CF₃O H H none none 164N H CF₃ H H CH H H H C₆H₅ H none none 165N H CF₃ H H CH H H 3-CF₃— H H none none C₆H₅O 166N H CF₃ H H CH H H CF₃O H H none none 167N H CF₃ H H CH H H C₆H₅O H H none none 168N CF₃ H CF₃ H CH H H CF₃O H H none none 169N CF₃ H CF₃ H CH H H C₆H₅O H H none none 170N CF₃O H H H CH H H CF₃ H CF₃ none none 171N C₆H₅O H H H CH H H CF₃ H CF₃ none none 172N H C₆H₅O H H CH H H C₆H₅O H H none none 173N H CF₃O H H CH H H CF₃O H H none none 174N H CF₃O H H CH H H H C₆H₅O H none none 175N C₆H₅O H H H CH H H H C₆H₅O H none none 176N H C₆H₅O H H CH H H H OCF₃ H none none 177N H C₆H₅O H H CH H H H C₆H₅O H none none 178N C₆H₅O H H H CH H H H CN H none none 179N C₆H₅O H H H CH H H CN H H none none 180N C₆H₅O H H H CH H H NO₂ H H none none 181N C₆H₅O H H H CH H H H NO₂ H none none 182N C₆H₅O H H H CH H H H SO₂CH₃ H none none 183N C₆H₅O H H H CH H H H 2-NO₂-4- H none none Cl—C₆H₃O 184N C₆H₅O H H H CH H H 4-Cl—C₆H₄O H H none none 185N C₆H₅O H H H CH H H 3,4-Cl—C₆H₃O H H none none 186N C₆H₅O H H H CH H H 3-CF₃— H H none none C₆H₃O 187N C₆H₅O H H H CH H H 3,5-Cl—C₆H₃O H H none none 188N C₆H₅O H H H CH H H H CH₃O H none none 189N C₆H₅O H H H CH H H H CO₂CH₃ H none none 190N C₆H₅O H H H CH H H 3-CH₃O H H none none C₆H₅O 191N C₆H₅O H H H CH H H 4-CH₃O H H none none C₆H₅O 193N C₆H₅O H H H CH H H CO₂CH₃ H H none none 194N CN H H H CH H H OCF₃ H H none none 195N NO₂ H H H CH H H OCF₃ H H none none 196N H CN H H CH H H OCF₃ H H none none 197N H NO₂ H H CH H H OCF₃ H H none none 198N SO₂CH₃ H H H CH H H OCF₃ H H none none 199N H SO₂CH₃ H H CH H H OCF₃ H H none none 200N H 4-F—C₆H₅ H H CH H H OCF₃ H H none none SO₂ 201N SO₂N H H H CH H H OCF₃ H H none none (CH₃)₂ 202N H SO₂N H H CH H H OCF₃ H H none none (CH₃)₂ 203N H CONH₂ H H CH H H OCF₃ H H none none 204N H CONH— H H CH H H OCF₃ H H none none C₆H₅ 205N H CO₂CH₃ H H CH H H OCF₃ H H none none 206N H CO₂C₄H₉ H H CH H H OCF₃ H H none none 207N H 4-Cl—C₆H₅ H H CH H H C₆H₅O H H none none 208N H 4-CF₃O— H H CH H H CF₃O H H none none C₆H₅ 209N 4-F—C₆H₄O H H H CH H H CF₃O H H none none 210N C₆F₅O H H H CH H H CF₃O H H none none 211N H 4-F—C₆H₅ H H CH H H CF₃O H H none none 212N H 4-CN—C₆H₅ H H CH H H CF₃O H H none none 213N H 4-C₆H₅— H H CH H H CF₃O H H none none C₆H₅ 214N C₆H₅O H H H CH CH₃ H CF₃O H H none none 215N C₆H₅O H H H CH CH₃ H NO₂ H H none none 216N C₆H₅O H H H CH CH₃ H H CN H none none 217N C₆H₅O H H H CH 3-CF₃ H CF₃ H H none none C₆H₅ 218N C₆H₅O H H H CH C₆H₅ H H C₆H₅ H none none 219N C₆H₅O H H H CH C₆H₅ H CF₃ H H none none 220N C₆H₅O H H H CH CH₃ H F H H none none 221N C₆H₅O H H H CH CF₃ H H H H none none 222N bond to —O— of R₆ aryl group

H H CH H H CF₃O H H none none 223N to CH₂ of R₆ aryl group

H H CH H H CF₃O H H none none 224N C₆H₅O H H H CH H H OCF₂CF₂H H H none none 225N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 226N 4-F—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 227N 3,4-Cl— H H H CH H H OCF₂CF₂H H H none none C₆H₅O 228N H C₆H₅ H H CH H H OCF₂CF₂H H H none none 229N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₂H H H none none 230N H 4-F—C₆H₅ H H CH H H OCF₂CF₂H H H none none 231N H 4-Br—C₆H₅ H H CH H H OCF₂CF₂H H H none none 232N 4-Br—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 233N C₆H₅O H H H CH H H OCF₂CF₃ H H none none 234N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₃ H H none none 235N 4-F—C₆H₅O H H H CH H H OCF₂CF₃ H H none none 236N 3,4-Cl— H H H CH H H OCF₂CF₃ H H none none C₆H₅O 237N H C₆H₅ H H CH H H OCF₂CF₃ H H none none 238N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₃ H H none none 239N H 4-F—C₆H₅ H H CH H H OCF₂CF₃ H H none none 240N H 4-Br—C₆H₅ H H CH H H OCF₂CF₃ H H none none 241N 4-Br—C₆H₅O H H H CH H H OCF₂CF₃ H H none none 242N C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 243N 4-Cl—C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 244N 4-F—C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 245N 3,4-Cl— H H H CH H H OCCl₂CCl₂H H H none none C₆H₅O 246N H C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 247N H 4-Cl—C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 248N H 4-F—C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 249N H 4-Br—C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 250N 4-Br—C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 251N C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 252N 4-Cl—C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 253N 4-F—C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 254N 3,4-Cl— H H H CH H H OCCl₂CCl₃ H H none none C₆H₅O 255N H C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 256N H 4-Cl—C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 257N H 4-F—C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 258N H 4-Br—C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 259N 4-Br—C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 260N C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 261N 4-Cl—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 262N 4-F—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 263N 3,4-Cl— H H H CH H H OCCl₂CF₃ H H none none C₆H₅O 264N H C₆H₅ H H CH H H OCCl₂CF₃ H H none none 265N H 4-Cl—C₆H₅ H H CH H H OCCl₂CF₃ H H none none 266N H 4-F—C₆H₅ H H CH H H OCCl₂CF₃ H H none none 267N H 4-Br—C₆H₅ H H CH H H OCCl₂CF₃ H H none none 268N 4-Br—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 269N C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 270N 4-Cl—C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 271N 4-F—C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 272N 3,4-Cl— H H H CH H H OCF₂CCl₃ H H none none C₆H₅O 273N H C₆H₅ H H CH H H OCF₂CCl₃ H H none none 274N H 4-Cl—C₆H₅ H H CH H H OCF₂CCl₃ H H none none 275N H 4-F—C₆H₅ H H CH H H OCF₂CCl₃ H H none none 276N H 4-Br—C₆H₅ H H CH H H OCF₂CCl₃ H H none none 277N 4-Br—C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 278N C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 279N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 280N 4-F—C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 281N 3,4-Cl— H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none C₆H₅O 282N H C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 283N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 284N H 4-F—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 285N H 4-Br—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 286N 4-Br—C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 287N C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 288N 4-Cl—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 289N 4-F—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 290N 3,4-Cl— H H H CH H H OCF₃ OCF₃ H none none C₆H₅O 291N H C₆H₅ H H CH H H OCF₃ OCF₃ H none none 292N H 4-Cl—C₆H₅ H H CH H H OCF₃ OCF₃ H none none 293N H 4-F—C₆H₅ H H CH H H OCF₃ OCF₃ H none none 294N H 4-Br—C₆H₅ H H CH H H OCF₃ OCF₃ H none none 295N 4-Br—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 296N C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 297N 4-Cl—C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 298N 4-F—C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 299N 3,4-Cl— H H H CH H H OCF₂H OCF₂H H none none C₆H₅O 300N H C₆H₅ H H CH H H OCF₂H OCF₂H H none none 301N H 4-Cl—C₆H₅ H H CH H H OCF₂H OCF₂H H none none 302N H 4-F—C₆H₅ H H CH H H OCF₂H OCF₂H H none none 303N H 4-Br—C₆H₅ H H CH H H OCF₂H OCF₂H H none none 304N 4-Br—C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 305N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 306N 4-Cl—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 307N 4-F—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 308N 3,4-Cl— H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none C₆H₅O 309N H C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 310N H 4-Cl—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 311N H 4-F—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 312N H 4-Br—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 313N 4-Br—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 314N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 315N 4-Cl—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 316N 4-F—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 317N 3,4-Cl— H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none C₆H₅O 318N H C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 319N H 4-Cl—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 320N H 4-F—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 321N H 4-Br—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 322N 4-Br—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 323N H H H H CH H H OH H H none none 324N H H H H CH H H OH OH H none none 325N H H H H CH H H H OH H none none 326N H H H H CH H H OCH₂CF₃ H H none none 327N H H H H CH H H H OCH₂CF₃ H none none 328N H H H H CH H H OCH₂CF₂CF₃ H H none none 329N H H H H CH H H OCH₂CH₂CF₃ H H none none 330N H H H H CH H H OCH(CF₃)₃ H H none none 331N H 4-F—C₆H₅O H H CH H H H H H none none 332N 4-F—C₆H₅O H H H CH H H H H H none none 333N H cyclo- H H CH H H H H H none none hexoxy 334N cyclo-hexoxy H H H CH H H H H H none none 335N H C(CH₃)₃ H H CH H H H H H none none 336N F H H H CH H H

bond to indicated phenyl carbon of R₁₀ subst. H none none

TABLE 5 Structure of “Secondary Phenyl Amine” Reagents (Y and Z each equal CH; R₇, R₈, R₁₂, R₁₃, R₁₄, and R₁₅ each equal H).

Secondary Phenyl Amine (XIII-A) Reagent Number R₄ R₅ R₆ R₉ R₁₀ R₁₁  1DB H OCF₃ H H OCF₃ H  2DB H Cl H H H CF₃  3DB H Br H H OCF₃ H  4DB H Cl H H OCF₃ H  5DB H Cl H H CF₃ H  6DB H H Cl H CF₃ H  7DB H F H H OCF₃ H  8DB H H Cl H H CF₃  9DB H F H H H CF₃ 10DB H H F H H CF₃ 11DB F H H H H CF₃ 12DB H Cl H CF₃ H H 13DB H H Cl CF₃ H H 14DB Cl H H CF₃ H H 15DB H F H CH₃ H H 16DB H H F H H CH₃ 17DB H F H H CH₃ H 18DB F H H CH₃ H H 19DB H H F H CH₃ H 20DB F H H H H CH₃ 21DB F H H H CF₃ H 22DB Cl H H H CF₃ H 23DB H F H CF₃ H H 24DB H H F CF₃ H H 25DB H F H H CF₃ H 26DB H H F H CF₃ H 27DB H OCF₃ H H H OCF₃

halide, alkyl benzenesulfonate such as a alkyl tosylate, alkyl mesylate, alkyl triflate or similar alkylating reagent of the general structure,

where M is a readily displaceable group such as chloride, bromide, iodide, tosylate, triflate, and mesylate. After allowing the reaction mixture to warm to room temperature, the reaction product is added to water, neutralized if necessary, and extracted with a water-immiscible solvent such as diethyl ether or methylene chloride. The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO4 and concentrated in vacuo to yield crude Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”) and Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”), wherein A and Q are independently aryl and heteroaryl. This material is purified, for example, by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”) and Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”). Products are tested for purity by HPLC. If necessary, Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”) and Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”) compounds are purified by additional chromatography or recrystallization. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”) and Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”) compounds prepared are summarized in Tables 6 and 7.

TABLE 6 Structure of Substituted Phenyl tertiary-omega-Hydroxyalkylamines (Y is CH; R₈, R₉, R₁₂, R₁₃, R₁₄, and R₁₉ are each H; Z is covalent bond and R₁₅ is absent).

Inhibitor Number Column 1 + Column 2 Reagent Reagent R₁ n m R₂ R₃ R₄ R₅ R₆ R₇ R₁₀ R₁₁ 1A  1N CF₃ 1 2 H H H C₆H₅O H H OCF₂CF₂H H 1A  2N CF₃ 1 2 H H H OCF₃ H H OCF₂CF₂H H 1A  3N CF₃ 1 2 H H F H H F OCF₂CF₂H H 1A  4N CF₃ 1 2 H H H F H H OCF₂CF₂H H 1A  5N CF₃ 1 2 H H H C₆H₅O H H OCF₃ H 1A  6N CF₃ 1 2 H H H OCF₃ H H OCF₃ H 1A  7N CF₃ 1 2 H H H H phenyl H OCF₃ H 1A  8N CF₃ 1 2 H H H phenyl H H OCF₃ H 1A  9N CF₃ 1 2 H H H H H H OCF₃ H 1A 10N CF₃ 1 2 H H H Br H H OCF₃ H 1A 11N CF₃ 1 2 H H H CF₃ F H CF₃ H 1A 12N CF₃ 1 2 H H H CH₃ H H CF₃ H 1A 13N CF₃ 1 2 H H H CF₃ H H CF₃ H 1A 14N CF₃ 1 2 H H H CH₃ H H OCF₃ H 1A 15N CF₃ 1 2 H H H F F H OCF₃ H 1A 16N CF₃ 1 2 H H H Br H H CF₃ H 1A 17N CF₃ 1 2 H H H CF₃ F H OCF₃ H 1A 18N CF₃ 1 2 H H H F H H OCF₃ H 1A 19N CF₃ 1 2 H H H Cl H H OCF₃ H 1A 20N CF₃ 1 2 H H H F H H CF₃ H 1A 21N CF₃ 1 2 H H H F F H CF₃ H 1A 22N CF₃ 1 2 H H H Cl H H CF₃ H 1A 23N CF₃ 1 2 H H H F H H phenoxy H 1A 24N CF₃ 1 2 H H H CF₃ Cl H CH₃ H 1A 25N CF₃ 1 2 H H H CF₃ F H CH₃ H 1A 26N CF₃ 1 2 H H H H H H CF₃ H 1A 27N CF₃ 1 2 H H F F H H CF₃ H 1A 28N CF₃ 1 2 H H H H OCH₃ H CF₃ H 1A 29N CF₃ 1 2 H H H F F H CH₃ H 1A 30N CF₃ 1 2 H H H OCH₃ H H CH₃ H 1A 31N CF₃ 1 2 H H H H CH₃ H H H 1A 32N CF₃ 1 2 H H H Cl H H H H 1A 33N CF₃ 1 2 H H H F H H F H 1A 34N CF₃ 1 2 H H H H OCH₃ H CH₃ H 1A 35N CF₃ 1 2 H H H H H H H H 1A 36N CF₃ 1 2 H H H H CH₃ H CH₃ H 1A 37N CF₃ 1 2 H H H H Cl H H H 1A 38N CF₃ 1 2 H H H F H H 3-CF₃—phenoxy H 1A 39N CF₃ 1 2 H H H F H H 4-CH₃O—phenoxy H 1A 40N CF₃ 1 2 H H H F H H 4-Cl—phenoxy H 1A 41N CF₃ 1 2 H H H F H H H H 1A 42N CF₃ 1 2 H H H F H H CH₃ H 1A 43N CF₃ 1 2 H H H F H F CH₃ H 1A 44N CF₃ 1 2 H H F F H H CH₃ H 1A 45N CF₃ 1 2 H H H Cl H H CH₃ H 1A 46N CF₃ 1 2 H H H CH₃ H H CH₃ H 1A 48N CF₃ 1 2 H H H H CH₃ H CF₃ H 1A 51N CF₃ 1 2 H H H H CH₃ H F H 1A 52N CF₃ 1 2 H H H CF₃ H H F H 1A 53N CF₃ 1 2 H H H CF₃ H H CH₃ H 1A 54N CF₃ 1 2 H H H OCH₃ H H CF₃ H 1A 56N CF₃ 1 2 H H H H CH₃ H CF₃ H 1A 57N CF₃ 1 2 H H H C₆H₅O H H H OCF₃ 1A 58N CF₃ 1 2 H H H H H H H OCF₃ 1A 59N CF₃ 1 2 H H H OCF₃ H H H OCF₃ 1A 60N CF₃ 1 2 H H H CF₃ F H H CF₃ 1A 61N CF₃ 1 2 H H H H OCH₃ H H CF₃ 1A 62N CF₃ 1 2 H H H CH₃ H H H CF₃ 1A 63N CF₃ 1 2 H H H Cl H H H CF₃ 1A 64N CF₃ 1 2 H H H CF₃ H H H OCF₃ 1A 65N CF₃ 1 2 H H H F H H H OCF₃ 1A 66N CF₃ 1 2 H H H F H F H OCF₃ 1A 67N CF₃ 1 2 H H H Br H H H OCF₃ 1A 68N CF₃ 1 2 H H H Cl H H H OCF₃ 1A 69N CF₃ 1 2 H H H F F H H OCF₃ 1A 70N CF₃ 1 2 H H H F H H H phenyl 1A 71N CF₃ 1 2 H H H CH₃ H H H OCF₃ 1A 72N CF₃ 1 2 H H H F F H H CF₃ 1A 73N CF₃ 1 2 H H H Cl H H H CH₃ 1A 74N CF₃ 1 2 H H H OCH₃ H H H CH₃ 1A 75N CF₃ 1 2 H H H F H H H CH₃ 1A 76N CF₃ 1 2 H H F F H H H OCF₃ 1A 78N CF₃ 1 2 H H H H OCH₃ H H CH₃ 1A 79N CF₃ 1 2 H H H H CH₃ H H CH₃ 1A 80N CF₃ 1 2 H H H CH₃ H H H CH₃ 1A 82N CF₃ 1 2 H H H F F H H CH₃ 1A 83N CF₃ 1 2 H H H F H F H CH₃ 1A 84N CF₃ 1 2 H H F F H H H CH₃ 1A 85N CF₃ 1 2 H H F CF₃ H H H CH₃ 1A 86N CF₃ 1 2 H H H H CH₃ H H CF₃ 1A 88N CF₃ 1 2 H H H CF₃ H H H CH₃ 1A 90N CF₃ 1 2 H H H H CF₃ H H CH₃ 1A 92N CF₃ 1 2 H H H CF₃ F H H CH₃

TABLE 7 Structure of Substituted Phenyltertiary-omega-Heteroalkylamines (Z and Y are each CH; R₇, R₈, R₁₂, R₁₃, R₁₄, R₁₅ and R₁₉ are each H).

Inhibitor Number Column 1 + Column 2 Reagent Reagent R₁ n m R₂ R₃ R₄ R₅ R₆ R₉ R₁₀ R₁₁ 1A  1DB CF₃ 1 2 H H H OCF₃ H H OCF₃ H 1A  2DB CF₃ 1 2 H H H Cl H H H CF₃ 1A  3DB CF₃ 1 2 H H H Br H H OCF₃ H 1A  4DB CF₃ 1 2 H H H Cl H H OCF₃ H 1A  5DB CF₃ 1 2 H H H Cl H H CF₃ H 1A  6DB CF₃ 1 2 H H H H Cl H CF₃ H 1A  7DB CF₃ 1 2 H H H F H H OCF₃ H 1A  8DB CF₃ 1 2 H H H H Cl H H CF₃ 1A  9DB CF₃ 1 2 H H H F H H H CF₃ 1A 10DB CF₃ 1 2 H H H H F H H CF₃ 1A 11DB CF₃ 1 2 H H F H H H H CF₃ 1A 12DB CF₃ 1 2 H H H Cl H CF₃ H H 1A 13DB CF₃ 1 2 H H H H Cl CF₃ H H 1A 14DB CF₃ 1 2 H H Cl H H CF₃ H H 1A 15DB CF₃ 1 2 H H H F H CH₃ H H 1A 16DB CF₃ 1 2 H H H H F H H CH₃ 1A 17DB CF₃ 1 2 H H H F H H CH₃ H 1A 18DB CF₃ 1 2 H H F H H CH₃ H H 1A 19DB CF₃ 1 2 H H H H F H CH₃ H 1A 20DB CF₃ 1 2 H H F H H H H CH₃ 1A 21DB CF₃ 1 2 H H F H H H CF₃ H 1A 22DB CF₃ 1 2 H H Cl H H H CF₃ H 1A 23DB CF₃ 1 2 H H H F H CF₃ H H 1A 24DB CF₃ 1 2 H H H H F CF₃ H H 1A 25DB CF₃ 1 2 H H H F H H CF₃ H 1A 26DB CF₃ 1 2 H H H H F H CF₃ H 1A 27DB CF₃ 1 2 H H H OCF₃ H H H OCF₃

Compounds of Formula (XXX), which can be used to prepare the “Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines” compounds of Tables 6 and 7, are given in Table 2. Reagents 1a and 2a in Table 2 are prepared from the corresponding alcohols. The tosylates are readily obtained by reacting the corresponding alcohol with tosyl chloride using procedures found in House's Modern Synthetic Reactions, Chapter 7, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference.

A preferred procedure for Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-heteroalkylamine”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-heteroalkylamines”) compounds, wherein the 2-hetero group is a hydroxyl, is Method A of Scheme 2. Oxirane reagents useful in Method A are exemplified, but not limited to those in Table 1. Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) compounds are prepared by using “Generic Secondary Amine” amines, hydroxylamines, and hydrazines of Formula XIII prepared above with oxiranes of the type listed in Table 1 and represented by the general structure:

In some cases, the oxiranes are prepared by reaction of epoxidation reagents such as MCPBA and similar type reagents readily selectable by a person of skill-in-the-art with alkenes. Fieser and Fieser in Reagents for Organic Synthesis, John Wiley & Sons provides, along with cited references, numerous suitable epoxidation reagents and reaction conditions, which are incorporated herein by reference.

Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-heteroalkylamine”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-heteroalkylamines”) compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using appropriate aziridines and thirranes according to Method A of Scheme 2. Aziridine and thiirane reagents useful in Method A are exemplified, but not limited to those in Table 1. These Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-heteroalkylamine”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-heteroalkylamines”) compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using “Generic Secondary Amine” amines, hydroxylamines, and hydrazines of Formula XIII prepared above with aziridines and thiiranes of the type listed in Table 1 and represented by the general structure:

wherein X is selected from N and S and R₁₆ is hydrogen or another suitable group when X is N.

TABLE 1 Structure of Oxirane, Aziridine, and Thiirane Reagents.

Rgnt No. R₁₆ X R₁ R₂ R₃  1 — O CF₃ H H  2 — O CCl₃ H H  3 — O CF₃ CH₃ H  4 — O CF₃CF₂ H H  5 — O CF₃CF₂CF₂ H H  6 — O CF₃OCF₂CF₂ H H  7 — O CF₃CH₂ H H  8 — O CF₃ CHF₂ H  9 — O CF₃ H CF₃ 10 — O CF₃ CF₃ H 11 — O CF₃ C₆H₅ H 12 — O CCl₃ C₆H₅ H 13 — O CCl₃ Cyclopropyl H 14 — O CCl₃ CH₃ H 15 — O CCl₃ (CH₃)₂CH H 16 — O CHCl₂ H H 17 — O CHCl₂ Cl H 18 — O CF₃ H CH₃ 19 H N CF₃ CF₃ H 20 H N CF₃ H H 21 Benzyl N CF₃ H H 22 CH₃O N CF₃ H H 23 CH₃ N CF₃ H H 24 Benzyloxy N CF₃ H H 25 — S CF₃ H H 26 — S CF₃CF₂ H H 27 — O CCl₃CH₂ H H 28 — O CBr₃CH₂ H H 29 — O CHBr₂CH₂ H H 30 — O CBrCl₂ H H 31 — O CClF₂ H H 32 — O CCl₂F H H 33 — O CCl₃CCl₂ H H 43 — O FCH₂ H H 46 — O CF₃ R₂ + R₃ = (CH₂)₃ 47 — O CF₃ R₂ + R₃ = (CH₂)₄ 48 — O CHF₂ R₂ + R₃ = (CH₂)₄ 56 — O CBrF₂CClFCH₂ H H 57 — O HCF₂CF₂OCH₂ H H

TABLE 2 Structure and Source of Alcohol Reagents.

Reagent Number R₁ n M m R₂ R₃ X—R₁₆ Source of Reagent 1A CF₃ 1 OTs 2 H H OH Tosylation of alcohol from Justus Liebigs Ann. Chem. (1969), 720, 81-97. 2A CF₃CH₂CH₂ 1 OTs 1 H H OH Tosylation of alcohol from Z. Naturforsch., B: Chem. Sci. (1997), 52 (3). 413-418

A mixture of a “Generic Secondary Amine” amine, hydroxylamine, or hydrazine of Formula XIII and an oxirane of Formula XX are stirred and heated to 40-90° C. for 5 to 48 hours in a tightly capped or contained reaction vessel. A Lewis acid such as ytterbium triflate in acetonitrile may be added to speed up reaction and improve yield. When a Lewis acid is used, the reaction should be carried out under inert, anhydrous conditions using a blanket of dry nitrogen or argon gas. After cooling to room temperature and testing the reaction mixture for complete reaction by thin layer chromatography or high pressure liquid chromatography (hplc), the reaction product is added to water and extracted with a water immiscible solvent such as diethyl ether or methylene chloride. (Note: If the above analysis indicates that reaction is incomplete, heating should be resumed until complete with the optional addition of more of the oxirane). The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO₄ and concentrated in vacuo to yield crude Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamine”) compounds. This material is purified by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield the Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamine”). Products are tested for purity by HPLC. If necessary, the Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamine”) compounds are purified by additional chromatography or recrystallization. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine”) compounds prepared are summarized in Example Tables 1 through 54.

Specific Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-heteroalkylamine”) analogs of the “Polycyclic Aryl tertiary-2-hydroxyalkylamine” compounds summarized in Example Tables 1 through 54, wherein the hydroxyl or oxy group are replaced with an amino, substituted amino, aza, or thiol, can be prepared by using the appropriate aziridine reagents or thiirane reagents readily by adapting the procedures in the numerous specific Examples and Schemes disclosed in the present invention. Similarly, intermediates, in which the hydroxyl or oxy group of said intermediates are replaced with an amino, substituted amino, aza, or thiol, can be converted using the numerous specific Examples and Schemes disclosed in the present invention to other Formula VII (“Generic Substituted Polycyclic Aryl tertiary 2-heteroalkylamine”) analogs of the “Polycyclic Aryl tertiary-2-hydroxyalkylamine” compounds.

As summarized in the general Scheme 2 and specific descriptions above, Schemes 5, 6, 7, and 11 illustrate the principles of Scheme 2 for the preparation of specifically substituted “Generic Substituted Polycyclic Aryl Tertiary OmegaHydroxyalkylamines” (V) having 2 aryl groups, “Generic Substituted Polycyclic Aryl and Heteroaryl Tertiary OmegaHydroxyalkylamines” (V-H) having two aromatic substituents made up of 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups, “Generic Substituted Polycyclic Heteroaryl Tertiary 2-Hydroxyalkylamines” (VII-H) having two aromatic substituents made up of 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups, and “Generic Substituted Polycyclic Aryl Tertiary 2-Hydroxyalkylamines” (VII) having two aryl groups.

Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7 and 9 to 11. Schemes 45 to 50 detail such procedures to prepare tertiary oxyalkylamine compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XVL (“Generic Substituted Alkylamine”). Said halogenated, oxygen containing primary alkylamine XVL, formed in Schemes 45 and 48, is itself converted to secondary amines, VLX-H (“Heteroaryl Alkyl Amine) and VLX (“Phenyl Alkyl Amine”), using procedures disclosed above. Primary alkylamine XVL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH (“Heteroaryl Carbonyl”) and XI-A (“Phenyl Carbonyl”) with azeotropic distillation to form imines, VL-H (“Heteroaryl Imine”) and VL (“Phenyl Imine”). Said imines VL-H and VL are then reduced with or without prior isolation by Reduction Methods 1, 2 or 3 as disclosed above and in Schemes 1, 3, and 9 to yield secondary amines, VLX-H (“Heteroaryl Alkyl Amine) and VLX (”Phenyl Alkyl Amine”). Said secondary amine VLX-H can be converted according to Schemes 46 and 47 to VII-H (“Generic Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylamines”). Using Schemes 49 and 50, VLX can be converted to VII (“Generic Substituted Polycyclic Phenyl Tertiary 2-hydroxyalkylamines”). Compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting VLX-H with an aryl bromide or aralkyl bromide instead of using an heteroaryl bromide or heteroaralkyl bromide as described in Schemes 46 and 47. Similarly, compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting VLX with an heteroaryl bromide or heteroaralkyl bromide instead of using an aryl bromide or aralkyl bromide as described in Schemes 49 and 50.

Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7, 9 to 11, and 45 to 50. Schemes 56,58, and 59 detail alternate procedures to prepare tertiary oxyalkylamine compounds of the present invention by initial formation of an halogenated, oxygen containing secondary alkylamines VLX and VLXX (“Phenyl Alkylamines”) and VLXX-O (“Phenyl Oxy Alkylamines”). Said secondary alkylamines VLX and VLXX (“Phenyl Alkylamines”) and VLXX-O (“Phenyl Oxy Alkylamines”) can be converted according to Schemes 56, 58 and 59 to VII (“Generic Substituted Polycyclic Aryl Tertiary 2-hydroxyalkylamines”) and VII-H (“Generic Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylamines”) by reaction with appropriate aromatic halides such as aryl bromides and heteroaryl bromides as desired.

Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”) and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7, 9 to 11, 45 to 50, 56,58, and 59. Scheme 57 details another alternate procedure to prepare tertiary oxyalkylamine compounds of the present invention by reacting secondary amines XIII-A (“Secondary Phenyl Amine”) and XIIIA-H (“Secondary Heteroaryl Amine”) with a diazo ester. The intermediate glycinate tertiary amine can then be reduced, partially reoxidized to an aldehyde, and converted using a perfluoroalkyl trimethylsilyl compound (for example, trifluoromethyl-TMS) to the desired product, VII (“Generic Substituted Polycyclic Aryl Tertiary 2-hydroxyalkylamines”) and VII-H (“Generic Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylamines”).

Formula V (“Generic Substituted Polycyclic Aryl tertiary-3-hydroxyalkylamines”) and Formula V-H (“Generic Substituted Polycyclic Heteroaryl tertiary-3-hydroxyalkylamines”), in which the halogenated oxy containing alkyl side chain has three carbons between the amine and oxy group, can be prepared in a manner similar to procedures disclosed above and in Schemes 45 to 50. Schemes 30 to 35 detail such procedures to prepare tertiary 3-oxyalkylamine compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XL (“Generic Substituted Alkylamine”). Said halogenated, oxygen containing primary alkylamine XL, formed in Schemes 30 and 33, is itself converted to secondary amines, LX-H (“Heteroaryl Alkyl Amine) and LX (“Phenyl Alkyl Amine”), using procedures disclosed above. Primary alkylamine XL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH (“Heteroaryl Carbonyl”) and XI-A (“Phenyl Carbonyl”) with azeotropic distillation to form imines, L-H (“Heteroaryl Imine”) and L (“Phenyl Imine”). Said imines L-H and L are then reduced with or without prior isolation by Reduction Methods 1, 2 or 3 as disclosed above and in Schemes 1, 3, and 9 to yield secondary amines, LX-H (“Heteroaryl Alkyl Amine) and LX (“Phenyl Alkyl Amine”). Said secondary amine LX-H can be converted according to Schemes 31 and 32 to V-H (“Generic Substituted Polycyclic Heteroaryl Tertiary 3-hydroxyalkylamines”). Using Schemes 34 and 35, LX can be converted to V (“Generic Substituted Polycyclic Phenyl Tertiary 3-hydroxyalkylamines”). Compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting LX-H with an aryl bromide instead of using an heteroaryl bromide as described in Schemes 31 and 32. Similarly, compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting LX with an heteroaryl bromide instead of using an aryl bromide as described in Schemes 34 and 35.

A particularly useful procedure to prepare Formula V-H (“Generic Substituted Polycyclic Heteroaryl tertiary-3-hydroxyalkylamines”) and VII-H (“Generic Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylamines”) compounds of the present invention in which the heteroaryl group is directly bonded is disclosed in Schemes 51 to 54. An halogenated, oxygen containing primary alkylamine XVL (“Generic Substituted Alkylamine”) formed in Schemes 45 and 48 is itself converted by reaction with LXXI-AH (“Heteroaryl Halide”) to afford secondary amine VLXX-H (“Heteroaryl Secondary Amine) using procedures disclosed in Scheme 51 and above. VLXX-H is converted to VII-H (“Generic Substituted Polycyclic Phenyl Heteroaryl Tertiary 2-hydroxyalkylamine”) by alkylation chemistry with an aralkyl bromide or aralkyloxyalkyl bromide using either of two procedures disclosed in Scheme 52. Isolation and purification is effected as disclosed previously. An halogenated, oxygen containing primary alkylamine XL (“Generic Substituted Alkylamine”) formed in Schemes 30 and 33 is itself also converted by reaction with LXXI-AH (“Heteroaryl Halide”) to afford secondary amine LXX-H (“Heteroaryl Secondary Amine) using procedures disclosed in Scheme 53 and above. LXX-H is converted to V-H (“Generic Substituted Polycyclic Phenyl Heteroaryl Tertiary 3-hydroxyalkylamine”) by alkylation chemistry disclosed in Scheme 54 and previously and as given above with reference to Scheme 52. Isolation and purification of V-H and VII-H are effected as disclosed previously.

Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”), Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”), and Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) can themselves serve as intermediates for conversion to additional compounds of this invention. Compounds of Formula VII and the present invention useful as intermediates include those in which the R₇ position substituent in Formula VII (“Generic Substituted Polycyclic Aryl Tertiary 2-hydroxyalkylamine”) is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other preferred compounds of Formula VII and the present invention useful as intermediates include those in which the R₁₀ position substituent in Formula VII is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other compounds of Formula VII and the present invention useful as intermediates include those in which one or more of R₆, R₇, R₁₁, and R₁₂ substituents in Formula VII is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.

Scheme 8 discloses the conversion of a 3-bromo substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine”) by reaction with a phenol to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 12 discloses the conversion of a 3-bromo substituent at the R₇ position in Formula VII-H (“Generic Substituted Polycyclic 3-Bromoheteroaryl Tertiary 2-hydroxyalkylamine”) by reaction with a phenol to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII-H (“Generic Substituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines”).

Scheme 22 discloses the conversion of a 3-bromo substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine”) by reaction with an aryl borinate to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Phenylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 23 discloses the conversion of a 3-bromo substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine”) by reaction with a primary or secondary amine to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-R₂₂aminoaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 40 discloses the conversion of a 3-bromo substituent at the R₁₀ position in Formula VII (“Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine”) by reaction with an aryl borinate to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Phenylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 41 discloses the conversion of a 3-bromo substituent at the R₁₀ position in Formula VII (“Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine”) by reaction with a heteroaryl dibutyl tin compound to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Heteroarylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 21 discloses the conversion of a 3-bromomethyl substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Bromomethylaryl Tertiary 2-hydroxyalkylamine”) by reaction with an aryl borinate to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Arylmethylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 13 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula VII-H (“Generic Substituted Polycyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylamine”) by reaction with an aryl bromide or heteroaryl bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII-H (“Generic Substituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines”).

Scheme 14 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with an aryl bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 15 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula VII-H (“Generic Substituted Polycyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylamine”) by reaction with an aralkyl bromide or heteroaralkyl bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII-H (“Generic Substituted Polycyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl, 3-Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Tertiary 2-Hydroxyalkylamines”).

Scheme 16 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with an aralkyl bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Aralkyloxyaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 20 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with an R₁₇-bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-R₁₇-oxyaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 19 discloses the conversion of a 3-thio substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-thioaryl Tertiary 2-hydroxyalkylamine”) by reaction with an R₁₇-bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-R₁₇thiaaryl Tertiary 2-Hydroxyalkylamine”). “Generic Substituted Polycyclic 3-R₁₇thiaaryl Tertiary 2-Hydroxyalkylamines” can be oxidized to sulfonyl compounds of Formula VII (“Generic Substituted Polycyclic 3-R₇sulfonylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 24 discloses the conversion of a 3-nitro substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Nitroaryl Tertiary 2-hydroxyalkylamine”) by hydrogenation to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamine”). “Generic Substituted Polycyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamines” can be acylated to acyl amide compounds of Formula VII (“Generic Substituted Polycyclic 3-Acylaminoaryl Tertiary 2-Hydroxyalkylamine”).

Schemes 25 and 26 disclose the conversion of a 3-amino substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Aminoaryl Tertiary 2-hydroxyalkylamine”) by reaction with carbonyl compounds to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-(Saturated Nitrogen Heterocycl-1yl)aryl Tertiary 2-Hydroxyalkylamine” and “Generic Substituted Polycyclic 3-(Unsaturated Nitrogen Heterocycl-1yl)aryl Tertiary 2-Hydroxyalkylamine”, respectively).

Scheme 27 discloses the conversion of a 3-methoxycarbonyl substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with amination reagents to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Carboxamidoaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 28 discloses the conversion of a 3-cyano substituent at the R₇ position in Formula VII (“Generic Substituted Polycyclic 3-Cyanoaryl Tertiary 2-hydroxyalkylamine”) by reaction with organometallic reagents to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Acylaryl Tertiary 2-Hydroxyalkylamine”). Said “Generic Substituted Polycyclic 3-Acylaryl Tertiary 2-Hydroxyalkylamines”, according to Scheme 29 can be reduced to hydroxyl compounds of Formula VII (“Generic Substituted Polycyclic 3-Hydroxysubstitutedmethylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 36 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula VII (“Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with amination reagents to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Carboxamidoaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 37 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula VII (“Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with an organometallic reagent to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-(bis-R₂₀-hydroxymethyl)aryl Tertiary 2-Hydroxyalkylamine”).

Scheme 38 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula VII (“Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with lithium aluminum hydride to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-Hydroxymethylaryl Tertiary 2-Hydroxyalkylamine”).

Scheme 39 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula VII (“Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with an alkylation reagent to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-(bis-R₂₁-hydroxymethyl)aryl Tertiary 2-Hydroxyalkylamine”).

Scheme 55 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula VII (“Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction intially with an amidation reagent and then an R₂₀-organometallic reagent to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (“Generic Substituted Polycyclic 3-(R₂₀-carbonyl)aryl Tertiary 2-Hydroxyalkylamine”).

Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”), Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”), Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. The hydroxyl group X, wherein R₁₆ is a hydrogen, of compounds of Formulas V, V-H, VII, and VII-H can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. In like manner, compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one hydroxyl group present in the form of an alcohol or phenol can be acylated to its corresponding esters. Similarly, carbamic acid esters (urethans) can be obtained by reacting any hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide. Suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII are available from commerical sources or the references cited above, which are incorporated herein by reference.

Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”), Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”), Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety derivatives. The hydroxyl group X, wherein R₁₆ is a hydrogen, of compounds of Formulas V, V-H, VII, and VII-H can be readily converted to ethers. Alkylation to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents, amine catalyst such as pyridine in an inert solvent. In like manner, compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one hydroxyl group present in the form of an alcohol or phenol can be alkylated to their corresponding ethers. Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one primary, secondary or tertiary amine group present can be converted to the corresponding quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, and sulfonates analogous to those used with alcohols and phenols. Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. Tertiary amines can be prepared from the corresponding primary or secondary amine by reductive alkylation with aldehydes and ketones using reduction methods 1, 2, or 3 as shown in Scheme 3. Suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivative hydroxyl, thiol, and amines of compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII are available from commerical sources or the references cited above, which are incorporated herein by reference.

Formula V-H (“Generic Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylamines”), Formula V (“Generic Substituted Polycyclic Aryl tertiary omegahydroxyalkylamines”), Formula VII (“Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines”), Formula VII-H (“Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines”) and certain other compounds of this invention can be converted, according to Schemes 17 and 18, to the corresponding cyclic derivatives represented by the general designation “Tricyclic tertiary-oxyalkylamines” exmplifled by Formula Cyclo-VII (“Substituted Tricyclic Phenyl tertiary-2-oxyalkylamines”). The hydroxyl group X, wherein R₁₆ is a hydrogen of compounds of Formulas V, V-H, VII, and VII-H can be cyclized to corresponding cyclic ethers. Compounds suitable for cyclization will normally have at least one leaving group within 5 to 10 continuous atoms of the hydroxyl group X wherein R₁₆ is a hydrogen. Most preferrably the leaving group will be within 5 to 7 atoms of the hydroxyl group X so as to form a 5 to 7 membered ring heteroatom containing ring. When the leaving group is part of an aromatic ring system, the leaving group will be preferrably in an ortho position. Suitable leaving groups generally include halides, sulfates, sulfonates, trisubsituted amino, disubstituted sulfonium, diazonium, and like, and, in the case of aromatic systems, also includes nitro, alkoxy, aryloxy, heteroaryloxy, and alkylthio. When X-R₁₆ is a thiol, amino, or substituted amino, the corresponding analogous sulfur and nitrogen analogs, Cyclo-VII (“Substituted Tricyclic Phenyl tertiary-2-thioalkylamines and tertiary-2-azaalkylamines”), of Formula Cyclo-VII (“Substituted Tricyclic Phenyl tertiary-2-oxyalkylamines”) can be obtained.

The cyclization reaction to form “Tricyclic tertiary-oxyalkylamines” can be accomplished by aromatic and aliphatic nucleophilic substitution reactions such as those disclosed in March's Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, especially at pages 293-412 and 649-658 and the references cited therein, which are incorporated herein by reference. Hydroxyl containing suitably substituted compounds can be converted to a cyclic analog by heating a suitably substituted compound under anhydrous conditions in a suitable solvent, such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetraglyme, or hexamethylphosphoramide, in the presence of a suitable base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium tertiary-butoxide, or lithium diisopropylamide. Alternately, sodium amide in anhydrous ammonia solvent can be used. Temperatures in the range of −20° C. to 200° C. can be used for time periods of 30 minutes to more than 24 hours. The preferred temperature can be selected by standard synthetic chemical technique balancing maximum yield, maximum purity, cost, ease of isolation and operation, and time required. Isolation of the “Tricyclic tertiary-oxyalkylamines” can be effected as described above for other tertiary-oxyalkylamines. Representative “Tricyclic tertiary-oxyalkylamines” prepared using the methodology described above are included in Table 8.

The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

TABLE 8 Structure of Substituted Tricyclic tertiary-2-oxyalkylamines.

Y Z R₅ K₁—R₆ R₁₀ K₂—R₁₁ R₁₂ R₁₃ CH₂ — 4-chloro-3-ethylphenoxy C—H H C—CF₃ H H CH₂ — 4-chloro-3-ethylphenoxy N H C—CF₃ H H CH₂ — 4-chloro-3-ethylphenoxy C—H H C—H CF₃ H CH₂ — 4-chloro-3-ethy1phenoxy N H C—H CF₃ H CH₂ — 4-chloro-3-ethylphenoxy C—H H N CF₃ H — — 4-chloro-3-ethylphenoxy C—H H C—CF₃ H H — — 4-chloro-3-ethylphenoxy N H C—CF₃ H H — — 4-chloro-3-ethylphenoxy C—H H C—H CF₃ H — — 4-chloro-3-ethylphenoxy N H C—H CF₃ H — — 4-chloro-3-ethylphenoxy C—H H N CF₃ H Structure of Substituted Tricyclic tertiary-2-oxyalkylamines.

Y Z R₇ K₁—R₆ R₁₀ K₂—R₁₁ R₅ R₈ CH₂ — 4-chloro-3-ethylphenoxy C—H OCF₂CF₂H C—H H H CH₂ — 4-chloro-3-ethylphenoxy N OCF₂CF₂H C—H H H CH₂ — 4-chloro-3-ethylphenoxy C—H OCF₂CF₂H N H H CH₂ — phenoxy C—H OCF₂CF₂H C—H H H CH₂ — phenoxy N OCF₂CF₂H C—H H H CH₂ — phenoxy C—H OCF₂CF₂H N H H CH₂ — 4-chloro-3-ethylphenoxy C—H CF₂CF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy N CF₂CF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy C—H CF₂CF₃ N H H CH₂ — phenoxy C—H CF₂CF₃ C—H H H CH₂ — phenoxy N CF₂CF₃ C—H H H CH₂ — phenoxy C—H CF₂CF₃ N H H CH₂ — 4-chloro-3-ethylphenoxy C—H CF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy N CF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy C—H CF₃ N H H CH₂ — phenoxy C—H CF₃ C—H H H CH₂ — phenoxy N CF₃ C—H H H CH₂ — phenoxy C—H CF₃ N H H CH₂ — 4-chloro-3-ethylphenoxy C—H OCF₂CF₂H C—H H F CH₂ — 4-chloro-3-ethylphenoxy N OCF₂CF₂H C—H H F CH₂ — 4-chloro-3-ethylphenoxy C—H OCF₂CF₂H N H F CH₂ — 4-chloro-3-ethylphenoxy C—H 2-furyl C—H H H CH₂ — 4-chloro-3-ethylphenoxy N 2-furyl C—H H H CH₂ — 4-chloro-3-ethylphenoxy C—H 2-furyl N H H CH₂ — 4-chloro-3-ethylphenoxy C—H SCF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy N SCF₃ C—H H H

R₂₂ is selected independently from any one or two of the following groups: hydrido, hydroxy, aryloxy, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkoxy, halocycloalkoxyalkyl, arylsulfinylalkyl, arylsulfonylalkyl, alkylamino cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, hydroxyalkyl, amino, alkoxy, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, heteroaryl, halocycloalkenyloxyalkyl, heteroarylalkyl, halocycloalkenyl, and heteroarylthioalkyl.

R₂₂ is selected independently from any one or two of the following groups: hydrido, hydroxy, aryloxy, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkoxy, halocycloalkoxyalkyl, heteroaryl, arylsulfinylalkyl, arylsulfonylalkyl, alkylamino cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, hydroxyalkyl, amino, alkoxy, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkenyl, halocycloalkenyloxyalkyl, heteroarylalkyl, and heteroarylthioalkyl.

VII: (Generic Substituted Polycyclic 3-Acylaryl Tertiary 2-Hydroxyalkylamine; R₁₆=H)

R₁₇ is selected from alkyl, alkenyl, alkynyl, aryl, aryloxyalkyl, aralkoxyalkyl, aralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, cycloalkenylalkyl, arylthioalkyl, aralkyl, and cycloalkenyl.

VII: (Generic Substituted Polycyclic 3-Acylaryl Tertiary 2-Hydroxyalkylamine; R₁₆=H)

R₁₇ is selected from alkyl, alkenyl, alkynyl, aryl, aryloxyalkyl, aralkoxyalkyl, aralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, aralkyl, heteroaralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, cycloalkenylalkyl, arylthioalkyl, and cycloalkenyl.

VII: (Generic Substituted Polycyclic 3-(bis-R₂₀-hydroxymethyl)aryl Tertiary 2-Hydroxyalkylamine; R₁₆=H)

R₂₀ is selected from alkyl, alkenyl, alkynyl, aryloxyalkyl, aralkoxyalkyl, aralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, aryl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, heteroaralkylthioalkyl, cycloalkenylalkyl, arylthioalkyl, aralkyl, alkoxyalkyl, alkylthioalkyl, and cycloalkenyl.

VII: (Generic Substituted Polycyclic 3-(R₂₀-carbonyl) Aryl Tertiary 2-Hydroxyalkylamine; R₁₆=H)

R₂₀ is selected from alkyl, alkenyl, alkynyl, aryl, aryloxyalkyl, aralkoxyalkyl, aralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, heteroaralkylthioalkyl, cycloalkenylalkyl, arylthioalkyl, aralkyl, alkoxyalkyl, and cycloalkenyl.

VII-H: (Generic Substituted Polycyclic Heteroaryl Tertiary 2-Hydroxyalkylamine) NOTE: Aryl Analogs (VII) Can Be Prepared by Starting With Secondary Phenyl Amine (XIII-A)

VII-H: (Generic Substituted Polycyclic Phenyl Heteroaryl Tertiary 2-Hydroxyalkylamine when R₁₆-X equals HO) NOTE: Aryl Analogs (VII) of (VII-H) Can Be Prepared by Starting With Aryl Bromide Analogs of (LXXI-AH).

VII-H: (Generic Substituted Polycyclic Phenyl Heteroaryl Tertiary 2-Hydroxyalkylamine when R₁₆-X=HO and Y=O) NOTE: Diaryl and Diheteroaryl Analogs Can Be Prepared by Using Aryl Bromide and Heteroaryl-OH, respectively.

The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the preceding schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized by ¹H NMR and mass spectrometry. These compounds also may be formed in vivo.

The following examples contain detailed descriptions of the methods of preparation of compounds of Formula V-H. These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated.

EXAMPLE 1

3-[(3-fluorophenyl)-[[3-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-1A) A solution of 3-fluoroaniline (1.92 mL, 0.02 mol) and trifluoro-m-tolualde-hyde (2.68 mL, 0.02 mol) in 30 mL of cyclohexane was refluxed using a Dean-Stark trap to remove water. After 4 hours, the cyclohexane was removed in vacuo to yield 5.4 g (100%) of the desired imine product as an amber oil. MS m/z=267 [M⁺]. ¹H NMR (CDCl₃) δ8.50 (s, 1H), 8.22 (s, 1H), 8.09 (d, 1H), 7.78 (d, 1H), 7.63 (t, 1H), 7.39 (dq, 1H), 6.99 (m, 3H). This imine (5.34 g, 0.02 mol) was then slurried in 30 mL of methanol at 0° C. Solid NaBH₄ (1.32 g, 0.0349 mol) was added in batches over 3 minutes at 0° C. The reaction was stirred below 10° C. for 30 minutes and then warmed gradually to 15° C. After 1 hour, the solution was cooled, and 3% aq. HCl solution was added until the aqueous layer was acidic. The aqueous solution was extracted twice with diethyl ether. The combined ether extracts were washed 3 times with brine, dried (MgSO₄), and concentrated in vacuo to yield 4.45 g (82%) of the desired N-(3-fluorophenyl)-[[3-(trifluoromethyl)phenyl]methyl]amine product as a light amber oil. MS m/z=269 [M⁺]. ¹H NMR (CDCl₃) δδ7.57 (m, 4H), 7.14 (dq, 1H), 6.45 (m, 2H), 6.33 (dt,1H), 4.41 (s, 2H), 4.27 (br, 1H).

The amine product EX-1A (2.69 g, 0.01 mol) was mixed with 3,3,3-trifluoro-1,2-epoxypropane (1.34 g, 0.012 mol), and the mixture was heated to 90° C. for 40 hours in a tightly capped vessel. After cooling to room temperature, the reaction product was purified by eluting through silica gel with 10% ethyl acetate in hexanes to yield 2.54 g (67%) of the desired aminopropanol as a light yellow oil, 100% pure product by GC and reverse phase HPLC. HRMS calcd. for C₁₇H₁₄F₇NO: 382.1042 [M+H]⁺, found: 382.1032. ¹H NMR (CDCl₃) δ7.47 (m, 4H), 7.19 (q, 1H), 6.50 (m, 3H), 4.50 (ABq, 2H), 4.39 (m,1H), 3.93 (dd, 1H), 3.60(dd, 1H), 2.51 (d, 1H).

Additional substituted 3-[(N-aryl)-[[aryl]methyl]amino]-halo-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Tables 1, 43, 46, and 47. Substituted 3-[(N-aralkyl)-[[aralkyl]amino]-halo-2-propanols can also be prepared by one skilled in the art using similar methods, as shown in Example Tables 2, 3, 44, and 45. Substituted 3-[(N-aryl)-[[aralkyl]amino]-halo-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 4. Substituted 3-[(N-aryl or N-aralkyl)-[[aryl]methyl]amino]-haloalkoxy-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Tables 5 and 48.

Example Table 1. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calc.* Obs.* No. R_(SUB1) R_(SUB2) Mass [M⁺] Mass [M⁺]  2 H H 295.1184 295.1180  3 3-OCH₃ 3-CH₃ 339.1446 339.1449  4 3-OCH₃ 4-CH₃ 339.1446 339.1444  5 4-CH₃ 3-CH₃ 323.1497 323.1491  6 4-OCH₃ 4-CH₃ 339.1446 339.1440  7 4-Cl H 329.0794 329.0783  8 4-CH₃ 4-CH₃ 323.1497 323.1495  9 3-Cl 3-CH₃ 343.0951 343.0950 10 3-F H 313.1090 313.1086 11 3-CH₃ 3-CH₃ 323.1497 323.1509 12 3-CH₃ 4-CH₃ 323.1497 323.1504 13 2-CH₃ 4-CH₃ 323.1497 323.1483 14 4-CH₃ H 309.1340 309.1331 15 2-CH₃ H 309.1340 309.1337 16 3-Cl H 329.0794 329.0794 17 3-F, 4-F 3-CH₃ 345.1152 345.1143 18 3-F 3-F 331.0996 331.0984 19 3-F, 4-F 3-CF₃ 399.0869 399.0827 20 4-CH₃ 3-CF₃ 377.1214 377.1180 21 2-CH₃ 3-CF₃ 377.1214 377.1176 22 3-F, 4-F 4-CF₃ 399.0869 399.0822 23 4-OCH₃ 4-CF₃ 393.1163 393.1159 24 3-F, 4-F 4-CH₃ 345.1152 345.1136 25 3-CH₃ 3-CF₃ 377.1214 377.1231 26 3-OCH₃ 4-CF₃ 393.1163 393.1179 27 2-CH₃ 3-CH₃ 323.1497 323.1486 28 4-OCH₃ 3-CH₃ 339.1446 339.1435 29 3-F, 5-F 4-CH₃ 345.1152 345.1159 30 3-Br 3-CF₃ 441.0163 441.0135 31 3-F 3-OCF₃ 397.0913 397.0894 32 4-CH₃ 3-F 327.1246 327.1291 33 3-F 4-CH₃ 328.1324 328.1333 34 3-Cl 4-CH₃ 344.1029 345.1045 35 H 3-CF₃ 364.1136 364.1122 36 3-Br 3-OCF₃ 458.0190 458.0145 37 4-CH₃ 4-CF₃ 378.1292 378.1259 38 3-Cl 3-CF₃ 398.0746 398.0727 39 3-CH₃ 4-CF₃ 378.1292 378.1274 40 2-CH₃ 4-CF₃ 378.1292 378.1259 41 3-Cl 3-OCF₃ 414.0695 414.0699 42 3-CF₃ 3-OCF₃ 448.0959 448.0961 43 3-F 3-OCF₂CF₂H 430.1053 430.1042 44 3-I 3-OCF₂CF₂H 538.0114 538.0077 45 3-CF₃ 4-CH₃ 378.1292 378.1296 46 3-CF₃ 3-F 382.1042 382.1073 47 3-CF₃ 3-CF₃ 432.1010 432.1026 48 3-OCH₃ 3-CF₃ 394.1241 394.1227 49 3-F 3-CH₃ 328.1324 328.1300 50 3-Cl 4-CF₃ 398.0746 398.0731 51 4-OCH₃ 3-CF₃ 394.1241 394.1237 52 3-CF₃, 4-F 3-CF₃ 450.0915 450.0913 53 3-CF₃, 4-F 4-CH₃ 396.1198 396.1179 54 3-CF₃ 4-OCF₃ 448.0959 448.0967 55 3-Cl 4-OCF₃ 414.0695 414.0690 56 3-F, 4-F 4-OCF₃ 416.0886 416.0904 57 3-F 4-OCF₃ 398.0991 398.0975 58 3-CF₃, 4-F 3-CH₃ 396.1197 396.1178 59 H 4-OCF₃ 380.1085 380.1077 60 3-OCF₃ 4-OCF₃ 464.0908 464.0877 61 3-CH₃ 4-OCF₃ 394.1241 394.1248 62 3-Br 4-OCF₃ 458.0189 458.0189 63 3-phenoxy 4-OCF₃ 472.1347 472.1344 64 3-F 3-phenoxy 406.1430 406.1418 65 3-F 4-phenyl 390.1481 390.1468 66 3-phenyl 3-OCF₃ 456.1397 456.1395 67 3-CF₃, 4-Cl 3-CH₃ 412.0903 412.0892 68 3-F, 5-F 4-OCF 416.0896 416.0895 69 2-F, 3-F 3-CF₃ 400.0941 416.0956 70 2-F, 5-F 3-OCF₂CF₂H 448.0959 448.0940 71 3-OCF₃ 3-OCF₂CF₂H 496.0971 496.0959 72 3-CH₃ 3-OCF₃ 394.1241 394.1244 73 H 3-OCF₃ 380.1085 380.1075 74 3-OCF₃ 3-OCF₃ 464.0908 464.0898 75 3-CF₃, 4-F 4-CF₃ 450.0915 450.0906 76 3,4-(CH═CH)₂— 3-OCF₃ 430.1241 430.1253 77 3-phenoxy 3-OCF₃ 472.1347 472.1342 78 3-F, 4-F 3-OCF₃ 416.0896 416.0884 79 4-phenyl 3-OCF₃ 456.1398 456.1368 80 2-F, 3-F 4-OCF₃ 416.0897 416.0885 81 3-F, 5-F 3-CH₃ 346.1230 346.1246 82 3-OCF₃ 3-phenoxy 472.1347 472.1342 83 3-OCF₃ 3-benzyloxy 486.1504 486.1503 84 3-phenoxy 3-phenoxy 480.1786 480.1772 85 2-phenyl 3-phenoxy 464.1837 464.1821 86 4-phenyl 3-phenoxy 464.1837 464.1836 87 4-phenyl 3-OCF₂CF₂H 488.1460 488.1443 88 4-n-octyl 3-OCF₃ 492.2337 492.2341 89 3,4-(OCF₂CF₂O) 3-OCF₃ 510.0763 510.0747 90 4-F 3-OCF₃ 398.0991 398.1023 91 3-phenoxy 3-ethoxy 432.1787 432.1770 92 3-phenoxy 3-(4-Cl-phenoxy) 514.1397 514.1426 93 3-OCF₃ 3-(4-Cl-phenoxy) 506.0958 506.0971 94 3-phenoxy 3-(3,4-Cl₂—C₆H₃O) 548.1007 548.1002 95 3-OCF₃ 3-(3,4-Cl₂—C₆H₃O) 540.0568 540.0555 96 3-OCF₃ 3-(3,5-Cl₂—C₆H₃O) 540.0568 540.0568 97 3-OCF₃ 4-OCH₃ 502.1453 502.1466 98 3-OCF₃ 3-CF₃ 540.1221 540.1248 99 3-OCF₃ 3-benzyloxy, 516.161 516.1626 4-OCH₃ 100 3-OCF₃ 3,4-dibenzyloxy 592.1922 592.1915 101 3-OCF₃ 3-OCH₂CH₃ 424.1347 424.1331 102 3-OCF₃ 3-acetoxy 438.114 438.1142 103 3-OCF₃ 3-(2-OH-ethoxy) 440.1297 440.1302 104 3-OCF₃ 3-[(3-Cl, 2-OH)-n- 488.1063 488.1050 propoxy] 105 3-OCF₃ 3,4-(OCH₂CH₂O) 438.114 438.1142 106 3-OCF₃ 4-benzyloxy, 516.1609 516.1608 3-OCH₃ 107 3-OCF₃ 3,5-dibenzyloxy 592.1922 592.1903 108 3-CF₃ 3-(3-CF₃-phenoxy) 524.1372 524.1281 109 3-CF₃ 3-phenoxy 456.1398 456.1421 110 4-CF₃ 3-(3-CF₃-phenoxy) 524.1272 524.1259 111 4-CF₃ 3-phenoxy 456.1398 456.1415 112 4-CF₃ 3-OCF₃ 424.1347 424.1331 113 3-phenoxy 3-nitro 433.1375 433.1379 114 3-phenoxy 3-(3,5-Cl₂—C₆H₄O) 548.1007 548.1016 115 3-phenoxy 3-(3-CF₃-phenoxy) 548.166 548.1639 116 3-OCF₃ 3,4-dimethoxy 440.1296 420.1294 117 3-OCF₃ 3-OCH₂CH₃, 454.1453 454.1458 4-OCH₃ 118 3-OCF₃ 3,4-diacetoxy 496.1194 496.1183 119 3-OCF₃ 4-acetoxy, 3-OCH₃ 468.1245 468.1239 120 3-OCF₃ 4-n-butoxy 452.1584 452.1614 121 3-OCF₃ 3-OCH₃ 410.1191 410.1179 122 3-OCF₃ 4-OCH₃ 410.1191 410.1177 123 3-OCH₃ 3-OCH₃ 356.1473 356.1469 124 3-OCH₃ 3-OCF₃ 410.1191 410.1158 125 3-OCF₃ 4-n-propoxy 438.1503 438.1517 126 3-benzyloxy 3-OCF₃ 486.1504 486.1524 127 3-benzyloxy 3-phenoxy 494.1947 494.1956 128 3-ethoxy 3-OCF₃ 424.1347 424.1363 129 3,4-(OCH₂O) 3-OCF₃ 424.0983 424.0990 130 3,4-(OCH₂O) 3-phenoxy 432.1424 432.1432 131 3,4-(O(CH₂)₂O) 3-OCF₃ 438.1140 438.1165 132 3,4-dimethoxy 3-OCF₃ 440.1296 440.1319 133 4-phenoxy 3-OCF₃ 472.1347 472.1334 134 4-OCF₃ 3-OCF₃ 464.0908 464.0923 135 4-n-butoxy 3-OCF₃ 452.1660 452.1624 136 4-benzyl 3-OCF₃ 470.1554 470.1148 137 3-phenoxy 3,4-(OCH₂CH₂O) 446.1579 446.1583 138 3-OCF₃ 3,4-diethoxy 468.1609 468.1638 139 3,4-(O(CH₂)₃O) 3-OCF₃ 452.1297 452.1307 140 3-OCF₃ 4-CF₃ 448.0959 448.0985 141 4-phenyl 4-CF₃ 440.1449 440.1451 142 3-cyano 4-CF₃ 389.1089 389.1097 143 3-CF₃ 4-phenyl 440.1449 440.1444 144 4-CF₃ 4-phenyl 440.1449 440.1457 145 3-phenoxy 3-CF₃, 5-CF₃ 524.1272 524.1285 146 3-phenoxy 4-cyano 413.1477 413.149 147 3-phenoxy 3-cyano 413.1477 413.1493 148 3-phenoxy 4-nitro 433.1375 433.1398 149 3-phenoxy 3-CF₃ 456.1398 456.1414 150 3-phenoxy 4-CF₃ 456.1398 456.1394 151 4-phenoxy 3-phenoxy 480.1786 480.1794 152 3-OCF₃ 4-phenoxy 472.1347 472.1347 153 3-phenoxy 4-phenoxy 480.1786 480.1780 154 4-phenoxy 4-phenoxy 480.1786 480.1298 155 4-phenoxy 4-OCF₃ 472.1347 472.1338 156 3-phenoxy 4-SO₂CH₃ 466.1298 466.1253 157 3-phenoxy 4-CO₂CH₃ 446.1579 446.1569 158 3-OCF₃ 4-ethoxy 424.1347 424.1317 159 3-cyclopentoxy 3-OCF₃ 494.1766 494.1771 4-methoxy 160 3,4,5-trimethoxy 3-OCF₃ 470.1402 470.1408 161 3-phenoxy 3-(OC₆H₄-4-OCH₃) 510.1892 510.1881 162 3-cyano 3-OCF₃ 405.1038 405.1021 163 4-cyano 3-OCF₃ 405.1038 405.104 164 4-CO₂-n-C₄H₉ 3-OCF₃ 480.161 480.1594 165 4-(4-Cl-phenoxy) 3-phenoxy 514.1397 514.1407 166 3-(4-F-phenoxy) 3-OCF₃ 490.1253 490.1211 167 4-(4-CN-C₆H₄) 3-OCF₃ 481.135 481.1354 168 3-phenoxy 4-(OC₆H₄-4-OCH₃) 510.1892 510.1919 *Note: Calculated (Calc.) and Observed (Obs.) masses measured for Example Numbers 33 through 168 are [M + H]⁺.

Example Table 2. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calc.* Obs.* No. R_(SUB1) R_(SUB2) Mass [M⁺] Mass [M⁺] 169 3-F 4-CF₃ 395.1120 395.1107 170 4-F 4-CF₃ 395.1120 395.1113 171 2-F 4-CF₃ 395.1120 395.1102 172 3-Cl 4-CF₃ 411.0825 411.0779 173 4-Cl 4-CF₃ 411.0825 411.0756 174 2-Cl 4-CF₃ 411.0825 411.0779 175 3-Cl 2-CF₃ 411.0825 411.0753 176 4-Cl 2-CF₃ 411.0825 411.0754 177 2-Cl 2-CF₃ 411.0825 411.0760 178 3-F 4-CH₃ 341.1403 341.1384 179 4-F 4-CH₃ 341.1403 341.1369 180 3-F 3-CH₃ 341.1403 341.1372 181 2-F 4-CH₃ 341.1403 341.1391 182 4-F 3-CH₃ 341.1403 341.1365 183 2-F 3-CH₃ 341.1403 341.1359 184 2-F 3-CF₃ 395.1120 395.1094 185 3-Cl 3-CF₃ 411.0825 411.0767 186 4-Cl 3-CF₃ 411.0825 411.0770 187 2-Cl 3-CF₃ 411.0825 411.0759 188 3-F 2-CF₃ 395.1120 395.1071 189 4-F 2-CF₃ 395.1120 395.1119 190 3-F 3-CF₃ 395.1120 395.1096 191 4-F 3-CF₃ 395.1120 395.1124 192 3-OCF₃ 3-OCF₃ 478.1064 478.0157 193 3-Cl 3-OCF₃ 428.0852 428.0878 194 3-Br 3-OCF₃ 472.0346 472.0366 195 3-phenoxy 3-OCF₃ 486.1503 486.1507 196 4-phenyl 3-OCF₃ 470.1554 470.1566 197 3-nitro 3-OCF₃ 439.1092 439.1051 *Note: Calculated (Calc.) and Observed (Obs.) masses measured for Example Numbers 192 through 197 are [M + H]⁺.

Example Table 3. 3-[N-(aralkyl)-N-(aralkyl)amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H] 198 2-(3-F-phenyl)-ethyl 3-(OCF₂CF₂H)- 458.1364 458.1384 benzyl

Example Table 4. 3-[N-(aryl)-N-(aralkyl)amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H] 199 3-F-phenyl 2-fluorenylmethyl 402.1481 402.1501 200 3-F-phenyl 1-(4-OCH₃- 390.1430 390.1415 naphthyl)methyl 201 2-fluorenyl 3-OCF₃-benzyl 468.1398 468.1375 202 3-phenoxyphenyl 1-(4-CN-phenyl)-ethyl 427.1633 427.1627 203 3-phenoxyphenyl 1-(3-F-phenyl)-ethyl 420.1587 420.1584 204 2-(7-bromo- 3-OCF₃-benzyl 546.0503 546.0531 fluorenyl) 205 3-phenoxyphenyl 1-(3-nitro-phenyl)ethyl 447.1531 447.1554 206 3-phenoxyphenyl 1-(3-OCF₃-phenyl) 486.1503 486.151 ethyl 207 3-dibenzofuryl 3-(OCF₂CF₂H)benzyl 502.1253 502.1241

Example Table 5. 3-[N-(aryl or aralkyl)-N-(aralkyl)amino]-1-haloalkoxy-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H] 208 3-OCF₃-benzyl 3-OCF₃ 540.1232 540.1219 209 3-OCF₃-phenyl 3-OCF₃ 526.1076 526.1049 210 3-phenoxy-phenyl 3-OCF₃ 534.1473 534.1515 211 3-phenoxy-phenyl isopropoxy 508.2111 508.2112 212 3-phenoxy-phenyl 3-OCF₂CF₂H 566.1577 566.1604 213 3-phenoxy-phenyl 3-ethoxy 494.1954 494.1982

EXAMPLE 214

3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-214A) A solution of 3-(phenoxy)aniline (2.78 g, 15 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (3.33 g, 15 mmol) was prepared in 60 mL of dichloroethane. Acetic acid (0.92 mL, 16.05 mmol) and solid NaBH(OAc)₃ (4.13 g, 19.5 mmol) were added. The mixture was stirred at room temperature for 3 hours, then acidified with 1 N aqueous HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO₄, and evaporated to give 5.00 g (85%) of the desired N-(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=391.

Amine product EX-214A (3.13 g, 8 mmol) and 3,3,3-trifluoromethyl-1,2-epoxypropane (1.34 g, 12 mmol) were dissolved in 1.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.25 g, 0.4 mmol) was added, and the stirred solution was warmed to 50° C. for 1 hour under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:16) to give 2.85 g (71%) of the desired aminopropanol product as a light amber oil, 99% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.30 (m, 3H), 7.27 (t, 1H), 7.20 (m, 3H), 7.02 (s, 1H), 6.96 (m, 2H), 6.48 (dd, 1H), 6.41 (dd, 1H), 6.37 (m, 1H), 5.89 (tt, 1H), 4.64 (ABq, 2H), 4.34 (m, 1H), 3.87 (dd, 1H), 3.55(dd, 1H), 2.41 (bs, 1H). ¹⁹F NMR (CDCl₃) δ−79.3 (d, 3F), −88.6 (m, 2F), −137.2 (dt, 2F). HRMS calcd. for C₂₄H₂₁O₃NF₇: 504.1410 [M+H]⁺, found: 504.1425.

Additional examples of 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 6 and 7.

Example Table 6. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H] 215 3-OCH₃, 5-CF₃ 3-CF₃ 462.1115 462.1115 216 3-phenoxy 3-SCF₃ 488.1119 488.1116 217 3-phenoxy H 388.1524 388.1558 218 3-SO₂-phenyl 3-OCF₂CF₂H 552.1080 552.1095

Example Table 7. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1)-N-R_(SUB2) [M + H] [M + H] 219

322.1419 322.1426

EXAMPLE 220

N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)-benzenemethanamine

EX-220A) To a 1,2-dichloroethane (30 mL) solution of 3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (2.00 g, 9.0 mmol) was added 3-bromoaniline (0.98 mL, 9.0 mmol), NaB(OAc)₃H (2.48 g, 11.7 mmol) and acetic acid (0.57 mL, 10 mmol). The cloudy mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 3.27 g (96%) of the desired N-(3-bromophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a brown oil which was used without further purification. MS m/z=377 [M⁺].

EX-220B) To a dichloromethane (9 mL) solution of the EX-220A amine (3.27 g, 8.65 mmol) was added 1,1,1-trifluoro-2,3-epoxypropane (0.968 mL, 11.3 mmol) and Yb(OTf)₃ (0.536 g, 0.86 mmol). The cloudy mixture was stirred at room temperature for 24 hours, then diluted with diethyl ether. The organic layer was washed with water and brine, dried (MgSO₄) and evaporated to yield 4.20 g (99%) of the desired 3-[(3-bromophenyl)-[[3-(1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a pale brown oil which can be used without further purification. The formation of the desired product was confirmed by the presence of the alcohol peak (δ1.5, d) in the ¹H NMR spectrum (C₆D₆). An analytical sample was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give the desired pure product as a yellow oil. FABMS m/z=491 [M+H]⁺. ¹H NMR (CDCl₃) δ3.55-3.63 (m, 1H), 3.88 (dd, 1H), 4.36 (m, 1H), 4.69 (s, 2H), 5.914 (tt, 1H), 6.66 (dd, 1H), 6.92 (m, 2H), 7.06 (s, 1H), 7.09 (m, 3H), 7.36 (t, 1H).

To a dichloromethane (10 mL) solution of EX-220B aminopropanol (4.20 g, 8.57 mmol) was added tert-butyldimethylsilyl trifluoromethanesulfonate (3.0 mL, 13.1 mmol) and triethylamine (2.40 mL, 17.3 mmol). The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, and washed with saturated NaHCO₃ and brine.

The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica eluting with 2.5% EtOAc in hexane gave 3.0 g (58%) of the desired N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine product as a colorless oil. HRMS calcd for C₂₄H₂₉BrF₇NO₂Si: 606.1098 [M+H]⁺, found 606.1118. ¹H NMR (C₆D₆) δ−0.19 (s, 3H), −0.06 (s, 3H), 0.88 (s, 9H), 3.38 (m, 2H), 4.11 (s, 2H), 4.12 (q, 1H), 5.10 (tt, 1H), 6.33 (dd, 1H), 6.61 (d, 1H), 6.68 (t, 1H), 6.81 (m, 2H), 6.89 (m, 2H), 6.97 (t, 1H).

EXAMPLE 221

3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

A solution of N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine (75 mg, 0.124 mmol), cesium carbonate (81 mg, 0.248 mmol), 4-chloro-3-ethylphenol (44 mg, 0.358 mmol), copper triflate benzene complex (6.24 mg, 10 mol %), 1-naphthoic acid (43 mg, 0.248 mmol) in 2:1 toluene:dimethylacetamide (3.0 mL) was heated at 105° C. for 96 hours. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with 50-90% acetonitrile in water to afford 16.2 mg (23%) of the desired 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C₂₆H₂₃ClF₇NO₃: 566.1332 [M+H]⁺, found: 566.1332. ¹H NMR (CDCl₃) δ1.18 (t, 3H), 2.69 (q, 2H), 3.50-3.61 (m, 1H). 3.87 (dd, 1H), 4.28-4.39 (m, 1H), 4.63 (s, 2H), 5.88 (tt, 1H), 6.32-6.40 (m, 2H), 6.48 (dd, 1H), 6.69 (dd, 1H), 6.87 (d, 1H), 7.0-7.34 (m, 5H).

Additional examples of 3-[(3-aryloxyphenyl and heteroaryloxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 8 and 9. Additional examples of 3-[(3-arylthiophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 10.

Example Table 8. 3-[(3-Aryloxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 222 2-chloro 538.1019 538.1021 223 2-fluoro 522.1315 522.1310 224 2-fluoro, 4-CF₃ 590.1189 590.1155 225 2,3,5-trifluoro 558.1127 558.1109 226 3-N,N-dimethylamino 547.1831 547.1844 227 2-fluoro, 3-CF₃ 590.1189 590.1184 228 3-NHCOCH₃ 561.1624 561.1590 229 2,3-dichloro 572.0630 572.0653 230 2-chloro, 4-fluoro 556.0925 556.0891 231 2-chloro, 4-chloro 572.0630 572.0667 232 3-methyl, 5-ethyl 546.1879 546.1899 233 3-ethyl 532.1722 532.1706 234 3,5-dimethyl 532.1722 532.1705 235 2,5-difluoro 540.1221 540.1255 236 4-(perfluorophenyl)- 741.0796 741.0799 2,3,5,6-tetrafluoro-phenyl 237 2,3,4-trifluoro 558.1127 558.1161 238 2,3-difluoro 540.1221 540.1182 239 3-acetyl 546.1515 546.1549 240 3-fluoro 522.1315 522.1337 241 3,5-difluoro 540.1221 540.1217 242 4-fluoro, 3-methyl 536.1471 536.1480 243 4-propoxy 562.1828 562.1803 244 3-trifluoromethoxy 588.1232 588.1236 245 3-chloro, 4-fluoro 556.0925 556.0932 246 4-chloro, 3-fluoro 556.0925 556.0933 247 3,4,5-trimethyl 546.1879 546.1901 248 3-trifluoromethyl 572.1283 572.1265 249 3-isopropyl 546.1879 546.1878 250 4-isopropyl 546.1879 546.1899 251 4-butoxy 576.1958 576.1969 252 3-tert-butyl 560.2035 560.2055 253 4-isopropyl, 3-methyl 560.2035 560.2035 254 4-sec-butyl 560.2035 560.2051 255 4-(1,1-dimethyl-propyl) 574.2192 574.2208 256 3,4-dichloro 572.0630 572.0630 257 4-cyclopentyl 572.2035 572.2029 258 3,4-(CH₂)₄ 558.1879 558.1881 259 4-benzyl 594.1879 594.1906 260 4-phenyl 580.1722 580.1741 261 4-n-butyl 560.2036 560.2033 262 4-ethoxy 548.1672 548.1674 263 4-mercapto 536.1130 536.1163 264 3-phenyl 580.1723 580.1772 265 4-chloro, 2-fluoro 556.0926 556.0954 266 4-n-propyl 546.1879 546.1878 267 4-methylthio 550.1209 550.1251 268 3,5-dimethoxy 564.1623 564.1617 269 4-bromo 582.0716 582.0473 270 3-hydoxymethyl 564.1621 564.1617 271 3-methyl, 4-methylthio 564.1443 564.1476 272 4-chloro, 3,5-dimethyl 552.1176 552.1185 273 4-methoxy 533.1437 533.1458 274 3-methoxy 533.1437 533.1450 275 4-chloro 537.0942 537.0944 276 4-(imidazo-1-yl) 569.1549 569.1552 277 3,4-dimethyl 531.1644 531.1649 278 3-methyl 517.1488 517.1493 279 4-chloro, 3-methyl 551.1098 551.1101 280 4-ethoxy 547.1594 547.1594 281 4-methyl 517.1488 517.1495

Example Table 9. 3-[(3-Aryloxy and Heteroaryloxyphenyl)-[[3-(1,1,2,2- tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 282 6-methyl-3-pyridyl 518.1440 518.1452 283 2-pyridyl 504.1284 504.1284 284 3-isoquinolyl 555.1518 555.1513 285 2-naphthyl 554.1566 554.1578 286 3-pyridyl 505.1362 505.1369 287 5-chloro-3-pyridyl 539.0972 539.1002 288 5-indolyl 543.1519 543.1630 289 2-methyl-3-pyridyl 519.1518 519.1517

Example Table 10. 3-[(3-Arylthiophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Mass Observed Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 290 H 519.1518 519.1119 291 4-methoxy 549.1209 549.1216

EXAMPLE 292

3-[[3-[(4-methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

A mixture containing N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine (75 mg, 0.124 mmol), cesium carbonate (57.5 mg, 0.176 mmol), 4-methoxyaniline (18.6 mg, 0.151 mmol) tris(dibenzylideneacetone) dipalladium(0) (4.6 mg, 0.005 mmol), R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.7 mg, 0.0075 mmol) and toluene (2.5 mL) was heated to 95° C. in a sealed vial for 48 h. Tetrabutylammonium fluoride (1 M, THF, 0.372 mL, 0.372 mmol) was added, and the reaction was stirred at 23° C. for 1.5 h. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 49 mg (73%) of the desired 3-[[3-[(4-methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd for C₂₅H₂₃F₇N₂O₃: 532.1597, found: 532.1592 [M]⁺. ¹H NMR (CDCl₃) δ3.48-3.57 (m, 1H), 3.77 (s, 3H), 3.83 (dd, 1H), 4.33 (m, 1H), 4.59 (s, 2H), 5.87 (tt, 1H), 6.27 (m, 1H), 6.33 (bd, 1H), 6.86 (dd, 4H), 7.02-7.12 (m, 4H), 7.31 (t, 1H), 7.41 (m, 1H), 7.60 (m, 1H). ¹⁹F NMR (CDCl₃) δ−137.201 (d, 2F), −88.515 (s, 2F), −79.120 (s, 3F).

Additional examples of 3-[[3-(N-arylamino and N-alkyl-N-arylamino)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 11 and 12. Additional examples of 3-[[3-(piperidino)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 13.

Example Table 11. 3-[[3-(Arylamino)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M]⁺ Mass [M]⁺ 293 4-fluoro 520.1397 520.1389 294 H 502.1491 502.1473 295 4-trifluoromethyl 570.1365 570.1335 296 4-chloro 536.1102 536.1125 297 4-cyano 527.1444 527.1452 298 4-CO₂CH₂CH₃ 574.1703 574.1703 299 4-n-propyl 544.1961 544.1959 300 4-[[3-(4-methyl-phenyl)]- 660.1971 660.1969 1,2,4-oxadiazol-5-yl] 301 4-[COCH(CN)-CO₂CH₂CH₃] 641.1761 641.1755 302 3-cyano 527.1444 527.1448 303 3-CO₂CH₂CH₃ 574.1703 574.1668 304 3-chloro 536.1102 536.1102 305 3-methoxy 532.1597 532.1593 306 3,4,5,-trimethoxy 592.1703 592.1703 307 3,5-difluoro 538.1303 538.1329 308 4-trifluoromethoxy 586.1314 586.1314 309 3,4-dimethoxy 562.1703 562.1713 310 3-trifluoromethyl 570.1365 570.1332

Example Table 12. 3-[[3-(N-alkyl-N-Arylamino)phenyl]-[[3-(1,1,2,2- tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. Rsub₁ Rsub₂ Mass [M]⁺ Mass [M]⁺ 311 H 3-trifluoromethyl-benzyl 584.1522 584.1518 312 —CH₂CH₃ 3-methyl-phenyl 544.1961 544.1959 313 n-C₄H₉ 4-CO₂CH₂CH₃-phenyl 630.2329 630.2329 314 —(CH₂)₂CN 4-methyl-phenyl 569.1913 569.1920

Example Table 13. 3-[[3-(N-piperidino)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. Rsub₁ Rsub₂ Mass [M]⁺ [M]⁺ 315 H H 494.1804 494.1804 316 H benzyl 584.2274 584.2280 317 —OCH₂CH₂O— 552.1859 552.1863

EXAMPLE 318

3-[[3-[(4-methoxyphenyl)methylamino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of 3-[[3-[(4-methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (44.3 mg, 0.083 mmol) in tetrahydrofuran (1.0 mL), methyl iodide (6.21 μL, 0.099 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) were added. The dark solution was stirred at 23° C. for 2 h, then heated to 55° C. for 12 h. The reaction mixture was filtered through celite, and the residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 25.2 mg (55%) of the desired 3-[[3-[(4methoxyphenyl)methylamino]-phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd for C₂₆H₂₅F₇N₂O₃: 546.1753, found: 546.1750 [M]⁺. ¹H NMR (CDCl₃), δ3.54 (m, 1H), 3.38 (s, 3H), 3.65-3.80 (m, 4H), 4.59 (s, 2H), 5.90 (tt, 1H), 6.20 (d, 1H), 6.37 (d, 1H), 6.68 (s, 1H), 6.76 (d, 2H), 6.90-7.15 (m, 6H), 7.31 (t, 1H). ¹⁹F NMR (CDCl₃), δ−137.21 (d, 2F), −88.52 (s, 2F), −78.79 (s, 3F).

Additional examples of 3-[[3-[(4methoxyphenyl)alkylamino and haloalkylamino)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 14.

Example Table 14. 3-[[3-[(4-methoxyphenyl)alkylamino and haloalkylamino)phenyl]-[[3-(1,1, 2,2- tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. R_(sub) Mass [M]⁺ [M]⁺ 319 ethyl 560.1910 560.1910 320 —(CH₂)₃CF₃ 642.1940 642.1920

EXAMPLE 321

3-[[(5-chloro-2-thienyl)methyl][(3-trifluoromethoxy)phenyl]amino]-1,1,1-trifluoro-2-propanol

EX-321A) 3-Trifluoromethoxyaniline (23.81 g, 134.4 mmol) and 3,3,3-trifluoro-1,2-epoxypropane (3.76 g 33.6 mmol) were placed into a sealed tube and heated to 80° C. for 24 h. The excess aniline was removed by distillation (70° C. at 16.2 Torr) to give 8.6 g (88%) of the desired 3-[(3-trifluoromethoxyphenyl)amino]-1,1,1-trifluoro-2-propanol product as a light yellow oil. ¹H NMR (CDCl₃) δ3.29-3.37 (m, 1H), 3.55 (dd, 1H), 4.20 (m, 1H), 6.48-6.63 (m, 3H), 7.12 (t, 1H). ¹⁹F NMR (CDCl₃) δ−79.36 (s, 3F), −58.44 (s, 3F).

EX-321B) The aminopropanol (18.68 g, 64.6 mmol) from EX-321A and imidazole (10.99 g, 0.162 mmol) were dissolved in dimethylformamide (40.0 mL) and t-butyl-dimethylsilyl chloride (11.69 g, 77.6 mmol) was added in 3.0 g portions over 15 min. The reaction was stirred at 23° C. for 18 h. The reaction solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO₄) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to afford 17.08 g (66%) of the desired silylated N-(3-trifluoromethoxyphenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoro-propylamine product as a light golden oil. FABMS m/z=404 [M+H]⁺. ¹H NMR (CDCl₃) δ0.042 (s, 3H), 0.085 (s, 3H), 0.91 (s, 9H), 3.25-3.35 (m, 1H), 3.50 (dd, 1H), 4.10 (m, 1H), 6.40 (bs, 1H), 6.50 (dd, 1H), 6.59 (d, 1H), 7.17 (t, 1H).

EX-321C) The silylated aminopropanol (0.157 g, 0.40 mmol) from EX-321B was dissolved in tetrahydrofuran (150 μL) and cooled to 0° C. Potassium tert-butoxide (1.0 M, THF, 0.60 mL, 0.60 mmol) was added in one portion via syringe. The dark solution was stirred at 0° C. for five minutes. 2-Chloro-5-bromomethyl-thiophene (73.5 mg, 0.44 mmol) was added in one portion to the cooled solution. The reaction mixture was stirred at 0° C. for 15 minutes then warmed to 23° C. for 16 h. Tetrabutyl-ammonium fluoride (1.0 M, THF, 1.2 mL, 1.2 mmol) was added to the dark reaction mixture and stirring followed for 2 h at 23° C. The solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO₄) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-20% ethyl acetate in hexane to afford 63.4 mg (39%) of the desired 3-[[(5-chloro-2-thienyl)methyl][(3-trifluoromethoxy)phenyl]amino-1,1,1-trifluoro-2-propanol product as a light golden oil. HRMS calcd. for C₁₅H₁₂ClF₆NO₂S: 419.1518, found: 419.1527 [M]⁺. ¹H NMR (CDCl₃) δ3.50-3.56 (m, 1H), 3.77 (dd, 1H), 4.28 (m, 1H), 4.67 (s, 2H), 6.62-6.75 (m, 5H), 7.24 (t, 1H). ¹⁹F NMR (CDCl₃) δ−79.24 (s, 3F), −58.04 (s, 3F).

Additional examples of 3-[[(aralkyl and heteroaralkyl)][(3-trifluoromethoxy)-phenyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 15.

Example Table 15. 3-[[(aralkyl and heteroaralkyl)][(3-trifluoromethoxy)- phenyl]amino]-1,1,1-trifluoro-2-propanols.

Calc. Obs. Ex. Mol. Mass No. R_(SUB) Wt. [M]⁺ 322 3-iodo-benzyl 505 506 323 4-difluoromethoxy-benzyl 445 446 324 4-(2-cyanophenyl)-benzyl 480 481 325 3-CO₂CH₃-benzyl 437 438 326 2,3,5,6-tetrafluoro-4-methoxy- 481 482 benzyl 327 3-cyano-benzyl 404 405 328 3,5-difluoro-benzyl 415 416 329 2,4-difluoro-benzyl 415 416 330 2,6-difluoro-benzyl 415 416 331 4-nitro-benzyl 424 425 332 (1-napthyl)methyl 429 430 333 4-phenyl-benzyl 455 456 334 2-chloro-4,5-(OCH₂CH₂O)-benzyl 457 458 335 3-nitro-benzyl 424 425 336 4-phenoxy-butyl 437 438 337 3-phenyl-propyl 407 408 338 3-(4-methoxy)phenyl-propyl 437 438 339 2-methoxyphenacetyl 437 438 340 2-(2,5-dimethoxy-phenyl)- 467 468 2-oxoethyl 341 4-CO₂CH₃-benzyl 437 438 342 2-(anthraquinonyl)-methyl 509 510 343 perfluorobenzoyl 483 484 344 2-(3-indolyl)ethyl 432 433 345 3-pyridinylmethyl 380 381 346 (5-chloro-2-thienyl)-methyl 419 420 347 4-methoxy-benzyl 409 410 348 3-methoxy-benzyl 409 410 349 4-pyridinylmethyl 380 381 350 3,5-dimethoxy-benzyl 439 440 351 3-(phenyl)propenoyl 419 420 352 3-phenyl-2,3-propenyl 405 406 353 3,5-dimethoxy-benzoyl 453 454 354 2,4,5-trimethoxy-benzyl 469 470 355 2,5-dimethoxy-benzyl 439 440 356 3-CO₂H-benzyl 423 424 357 3-OH-benzyl 395 396 358 2,5-dihydroxy-benzyl 411 412 359 3,4,5-trihydroxy-benzyl 427 428 360 3,5,-dihydroxy-benzyl 411 412 361 2-(phenoxy)phenacetyl 499 500 362 2-quinolinylmethyl 430 431 363 2-pyridinylmethyl 380 381 364 2-benzimidazolyl-methyl 419 420 365 1-benzyl-2-imidazolyl-methyl 459 460 366 (2,6-dichioro-4- 449 450 pyridinyl)methyl

EXAMPLE 367

N′-(4-butoxyphenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-N-[3-(trifluoromethoxy)phenyl]urea

The silylated aminopropanol (0.150 g, 0.372 mmol) from EX-321B was dissolved in chloroform (0.5 mL). Then 4-n-butoxyphenyl isocyanate (78.25 mg, 0.409 mmol) was added, and the resulting solution was stirred at 23° C. in a sealed vial for 16 h followed by heating to 65° C. for 24 h. The reaction was cooled to 23° C., and a solution of tetrabutylammonium fluoride (1.0 M, THF, 0.5 mL, 0.50 mmol) was added to the reaction, which was then stirred at 23° C. for 2 h. The solution was diluted with ethyl acetate and washed with water and brine. The residue was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexane to afford 73.6 mg (38%) of the desired urea product as a pale yellow glass. FABMS m/z=481 [M+H]⁺. ¹H NMR (CDCl₃), δ0.99 (t, 3H), 1.484 (m, 2H), 1.740 (m, 2H), 3.25-3.35 (m, 1H), 3.55 (dd, 1H), 3.94 (m, 2H), 4.207 (m, 1H), 6.17 (s, 1H), 6.48 (s, 1H), 6.50-6.65 (m, 2H), 6.83 (d, 2H), 7.15 (d, 2H), 7.58 (t, 1H), ¹⁹F NMR (CDCl₃) δ−78.87 (s, 3F), −58.29 (s, 3F).

Additional examples of N′-(aryl and sulfonylaryl)-N-(3,3,3-trifluoro-2-hydroxy-propyl)-N-[3-(trifluoromethoxy)phenyl]ureas are prepared by one skilled in the art using similar methods, as shown in Example Table 16.

Example Table 16. N′-(aryl and sulfonylaryl)-N-(3,3,3-trifluoro-2- hydroxypropyl)-N-[3-(trifluoromethoxy)phenyl]ureas.

Ex. Calculated Observed No. R_(SUB) Mol. Wt. Mass [M]⁺ 368 2-CH₃S-phenyl 454 455 369 4-biphenyl 484 485 370 4-CH₃-phenyl-SO₂— 486 487

EXAMPLE 371

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol

EX-371A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) dissolved in 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture was stirred for 6 h, water was added, and the mixture was extracted with dichloromethane. The organics were washed with saturated aqueous sodium bicarbonate then dried over MgSO₄. The dried organic layer was evaporated to give 11.00 g (78%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol product as a dark orange oil. ¹H NMR (CDCl₃) δ4.32 (s, 2H), 5.88 (tt, 1H), 6.08 (t, 1H), 6.17-6.22 (m, 2H), 7.00 (t, 1H), 7.11 (dd, 1H), 7.24-7.27 (m, 2H), 7.33 (t, 1H).

A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol (11.0 g, 34.9 mmol), 3,3,3-trifluoro-1,2-epoxypropane (4.5 mL, 52.4 mmol) and ytterbium trifluoromethanesulfonate (2.2 g, 10 mol %) in 20 mL of acetonitrile was heated at 50° C. in a sealed glass tube for 16 h. The reaction mixture was cooled, water was added, and the reaction mixture was extracted with ether. The ether layer was washed with saturated aqueous sodium bicarbonate and brine and dried over MgSO₄. The dried organic layer was evaporated to give 8.07 g (89%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2hydroxypropyl)amino]phenol product as a yellow oil. HRMS calcd. for C₁₈H₁₇F₇NO₃: 428.1097 [M+H]⁺, found: 428.1104. ¹H NMR (CDCl₃) δ3.58 (dd, 1H), 3.88 (dd, 1H), 4.39 (m, 1H), 4.68 (s, 2H), 5.91 (tt, 1H), 6.25-6.37 (m, 3H), 7.07-7.14 (m, 4H), 7.35 (t, 1H).

EXAMPLE 372

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol), 3-trifluoromethoxybenzyl bromide (70.0 mg, 0.27 mmol) in 2.5 mL of acetone and cesium carbonate (100 mg, 0.31 mmol) were added. The reaction mixture was heated to 60° C. for 18 h then cooled. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 63.3 mg (45%) of the desired benzyl ether product as an orange oil. HRMS calcd. for C₂₆H₂₂F₁₀NO₄: 602.1389 [M+H]⁺, found: 602.1380. ¹H NMR (CDCl₃) δ3.61 (dd, 1H), 3.83 (dd, 1H), 4.32-4.39 (m, 1H), 4.62 (s, 2H), 4.98 (s, 2H), 5.84 (tt, 1H), 6.43-6.55 (m, 3H), 7.04-7.42 (m, 9H).

Additional examples of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl][3-[(substituted)methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods as shown in Example Tables 17 and 18.

Example Table 17 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]lmethyl[]3- [(substituted-phenyl)methoxy[phenyl[amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 373 H 518.1566 518.1578 374 4-trifluoromethoxy 602.1389 602.1383 375 4-nitro 563.1417 563.1457 376 2,3,4,5,6-pentafluoro 608.1095 608.1092 377 3,5-di(trifluoromethyl) 654.1314 654.1308 378 3,5-difluoro 554.1378 554.1390 379 3-trifluoromethyl 586.1440 586.1419 380 2,3,5,6-tetrafluoro-4-trifluoromethyl 658.1063 658.1003 381 4-fluoro-2-trifluoromethyl 604.1346 604.1321 382 3-nitro 563.1417 563.1416 383 3-cyano 543.1519 543.1523 384 4-cyano 543.1519 543.1517 385 4-methyl 532.1723 532.1729 386 2,3,5,6-tetrafluoro-4-methoxy 620.1295 620.1261 387 3-methoxycarbonyl 576.1621 576.1613 388 4-methoxycarbonyl 576.1621 576.1614 389 4-difluoromethoxy 584.1483 584.1480 390 2-fluoro 536.1472 536.1465 391 4-fluoro 536.1472 536.1454 392 2,4,6-trifluoro 572.1284 572.1267 393 3-chloro-2-fluoro 570.1082 570.1069 394 2-6-difluoro 554.1378 554.1385 395 2,4-difluoro 554.1378 554.1346 396 2,4-di(trifluoromethyl) 654.1314 654.1321 397 2,5-difluoro 554.1378 554.1350 398 3,4-difluoro 554.1378 554.1381 399 2,3-difluoro 554.1378 554.1364 400 2-fluoro-3-trifluoromethyl 604.1346 604.1329 401 3-bromo 596.0671 596.0641 402 3-methyl 532.1723 532.1692 403 2-bromo 596.0671 596.0666 404 2-chloro 552.1176 552.1175 405 3-iodo 644.0533 644.0517 406 3-fluoro 536.1472 536.1475 407 3-methoxy 548.1672 548.1676 408 2,3,5-trifluoro 572.1284 572.1276 409 4-trifluoromethylthio 618.1161 618.1165 410 3-trifluoromethylthio 618.1161 618.1151 411 3-fluoro-5-trifluoromethyl 604.1346 604.1309 412 4-fluoro-3-trifluoromethyl 604.1346 604.1336 413 4-(phenylmethoxy) 624.1985 624.1956 414 4-phenyl 594.1879 594.1845 415 4-ethyl 546.1879 546.1862 416 4-trifluoromethyl 586.1440 586.1400 417 2-methyl-3-nitro 577.1573 577.1576 418 4-tert-butyl 574.2192 574.2163 419 3,4-dimethyl 546.1879 546.1881 420 3-chloro 552.1176 552.1157 421 4-bromo 596.0671 596.0669 422 3,5-dichloro 586.1787 586.1378 423 3,5-dimethyl 546.1879 546.1890 424 4-chloro 552.1176 552.1188 425 2-fluoro-3-methyl 550.1628 550.1625 426 3-phenoxy 610.1828 610.1819 427 4-isopropyl 560.2036 560.2020

Example Table 18. 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl] [3-[(substituted)-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 428 3-pyridylmethyl 519.1519 519.1483 429 1-phenylethyl 532.1723 532.1711 430 1-benzylimidazol-2-ylmethyl 598.1941 598.1946 431 5-chlorobenzo[b]thien-3-ylmethyl 608.0897 608.0884 432 2-pyridylmethyl 519.1519 519.1522 433 4-pyridylmethyl 519.1519 519.1515

EXAMPLE 434

3-[[3-[(4-aminophenyl)methoxy]phenyl][[3-(1,1,2,2-tetrafluoro-thoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-434A) A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[(3-phenyl)methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol (42.0 mg, 0.07 mmol) and zinc dust (37 mg, 0.57 mmol) in acetic acid (0.5 mL) was stirred for 4 d. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 15.4 mg (39%) of the desired reduced amine product as a brown oil. HRMS calcd. for C₂₅H₂₄F₇N₂O₃: 533.1675 [M+H]⁺, found: 533.1656. ¹H NMR (acetone-d₆) δ3.60 (dd, 1H), 3.85 (m, 1H), 3.90 (s, 2H), 4.45 (m, 1H), 4.73 (s, 2H), 6.22-6.64 (m, 4H), 6.94 (dd, 1H), 7.12-7.45 (m, 9H).

EX-434B) 3-[[3-[(3-aminophenyl)methoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol is prepared by one skilled in the art using similar methods. HRMS calcd. for C₂₅H₂₄F₇N₂O₃: 533.1675 [M+H]⁺, found: 533.1654.

EXAMPLE 435

3-[[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]methyl]benzoic Acid

EX-435A) A solution of ethyl 3-[[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]methyl]benzoate (22.1 mg, 0.04 mmol) and lithium hydroxide (5 mg, 0.12 mmol) in water (1 mL) and tetrahydrofuran (0.5 mL) was heated at 80° C. for 16 h. The reaction mixture was added to 6 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 5.6 mg (19%) of the desired benzoic acid product as a brown oil. HRMS calcd. for C₂₆H₂₃F₇NO₅: 562.1464 [M+H]⁺, found: 562.1418. ¹H NMR (acetone-d₆) δ3.64 (dd, 1H), 3.95 (m, 1H), 4.45-4.50 (m, 1H), 4.80 (s, 2H), 5.12 (s, 2H), 6.27-6.63 (m, 4H), 7.06-7.27 (m, 4H), 7.41 (t, 1H), 7.50 (t, 1H), 7.66 (d, 1H), 7.99 (d, 1H), 8.10 (s, 1H).

EX-435B) 4-[[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]methyl]benzoic acid is prepared by one skilled in the art using similar methods. HRMS calcd. for C₂₆H₂₃F₇NO₅: 562.1464 [M+H]⁺, found: 562.1445.

EXAMPLE 436

3-[[3-(2-nitrophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol), 1-bromo-2-nitrobenzene (52.4 mg, 0.26 mmol), copper(I) trifluoromethanesulfonate benzene complex (3 mg, 2.5 mol %) and cesium carbonate (100 mg, 0.31 mmol) in toluene (1 mL) and ethyl acetate (1 mL) was heated at 95° C. in a sealed vial for 4 d. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 14.1 mg (11%) of the desired 2-nitrophenyl ether product as an orange oil. HRMS calcd. for C₂₄H₂₀F₇N₂O₅: 549.1260 [M+H]⁺, found: 549.1235. ¹H NMR (CDCl₃) δ3.63 (dd, 1H), 3.84 (dd, 1H), 4.35-4.42 (m, 1H) 4.64 (s, 2H), 5.90 (tt, 1H), 6.47-6.67 (m, 3H), 6.98-7.50 (m, 8H), 7.97 (d, 1H).

Additional examples of 3-[[3-aryloxyphenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 19.

Example Table 19. 3-[[3-aryloxyphenyl][[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Ex. Mass Observed No. R_(SUB) [M + H]⁺ Mass [M + H]⁺ 437 4-tert-butylphenyl 560.2036 560.2050 438 4-nitrophenyl 549.1260 549.1306 439 4-bromo-2-nitrophenyl 627.0366 627.0375 440 3-fluoro-2-nitrophenyl 567.1166 567.1135 441 2-cyano-3-pyridyl 530.1315 530.1300 442 5-carboxy-3-pyridyl 549.1260 549.1269 443 4-fluoro-2-pyridyl 523.1268 523.1243 444 3-trifluoromethyl-2-pyridyl 573.1236 573.1205 445 5-trifluoromethyl-2-pyridyl 573.1236 573.1197 446 5-bromo-2-pyridyl 583.0667 583.0405 447 2-methyl-5-nitrophenyl 563.1417 563.1416 448 thiazol-2-yl 511.0926 511.0911 449 5-pyrimidinyl 506.1315 506.1315

EXAMPLE 450

3-[[3-(4-aminophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol and 3-[[3-[4-(ethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol

A solution of 3-[[3-(4nitrophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol (33.8 mg, 0.06 mmol) in ethanol and 5% palladium on carbon (4 mL) was placed under 40 psi hydrogen gas for 7 h. The mixture was filtered through celite, the solvent was evaporated, and the residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give 13.4 mg (42%) of (EX-450A) as 3-[[3-(4-aminophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol and 13.9 mg (41%) of (EX-450B) as 3-[[3-[4-(ethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol both as orange oils. 3-[[3-(4-aminophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol: HRMS calcd. for C₂₄H₂₂F₇N₂O₃: 519.1519 [M+H]⁺, found: 519.1529. ¹H NMR (acetone-d₆) δ3.63 (dd, 1H), 3.96 (dd, 1H), 4.42-4.58 (m, 1H), 4.80 (s, 2H), 5.88 (m, 1H), 6.20 (m, 1H), 6.32-6.77 (m, 6H), 6.92 (d, 1H), 7.06-7.26 (m, 3H), 7.43 (m, 1H). 3-[[3-[4-(ethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol: HRMS calcd. for C₂₆H₂₆F₇N₂O₃: 547.1832 [M+H]⁺, found: 547.1819. ¹H NMR (acetone-d₆) δ1.23 (t, 3H), 3.17 (q, 2H), 3.63 (dd, 1H), 3.96 (dd, 1H), 4.42-4.58 (m, 1H), 4.79 (s, 2H), 5.85 (d, 1H), 6.20 (m, 1H), 6.33 (m, 1H), 6.47 (m, 1H), 6.50 (tt, 1J), 6.61 (d, 2H), 6.78 (d, 2H), 7.09 (t, 1H), 7.20 (m, 1H), 7.23 (d, 1H), 7.42 (m, 1H).

EXAMPLE 451

3-[[3-(2-pyridinyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

A solution of 3-[(3-bromophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (100 mg, 0.22 mmol), 2-tributylstannyl pyridine (96 mg, 0.26 mmol), dichlorobis(triphenylphospine)palladium(II) (6 mg, 6.7 mol %) and lithium chloride (46 mg, 1.09 mmol) in toluene (4 mL) was heated at 105° C. for 16 h. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to afford 47.7 mg (45%) of the desired pyridyl product as an orange oil. HRMS calcd. for C₂₃H₂₀F₇N₂O₂: 489.1377 [M+H]⁺, found: 489.1413. ¹H NMR (acetone-d₆) δ3.78 (dd, 1H), 4.06 (dd, 1H), 4.52-4.61 (m, 1H), 4.94 (s, 2H), 5.89 (d, 1H), 6.43 (tt, 1H), 6.94 (m, 1H), 7.18 (m, 1H), 7.22-7.42 (m, 5H), 7.60 (s, 1H), 7.80 (m, 2H), 8.61 (m, 1H).

Additional examples of 3-[[3-(heteroaryl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 20.

Example Table 20. 3-[[3-(heteroaryl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)- phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. R_(SUB) Mass [M + H]⁺ [M + H]⁺ 452 2-thienyl 494.1024 494.0987 453 2-furyl 478.1025 478.1025 454 3-pyridyl 489.1413 489.1391 455 3-methyl-2-pyridyl 503.1570 503.1531

EXAMPLE 456

1-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)benzoyl]piperidine

EX-456A) Ethyl 3-aminobenzoate (6.75 mL, 0.045 mol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (10 g, 45 mmol) were dissolved in 100 mL of dichloroethane and acetic acid (2.7 mL, 47 mmol), then solid NaBH(OAc)₃ (14.3 g, 67 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine, then dried over MgSO₄, and evaporated to give 16.7 g (98%) of the desired ethyl 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzoate product as a yellow oil. ¹H NMR (CDCl₃) δ1.3 (t, 3H), 4.3 (q, 2H), 4.5 (s, 2H), 6.5 (tt, 1H), 6.9 (d, 1H), 7.1-7.4 (m, 7H).

EX-456B) A solution of EX-456A (16.7 g, 45 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (4.26 mL, 49.5 mmol) were dissolved in 30 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (2.79 g, 4.5 mmol) was added, and the stirred solution was warmed to 50° C. for 18 hours. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, then dried over MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane to give 12 g (55%) of the desired ethyl 3-[[[3-(1,1,2,2-tetra-fluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]-benzoate product as a colorless oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₁H₂₁F₇NO₄: 484.1359 [M+H]⁺, found: 484.1342. ¹H NMR (CDCl₃) δ1.4 (t, 3H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 3H), 4.7 (dd, 2H), 5.9 (tt, 1H), 6.9 (d, 1H), 7.1-7.2 (m, 3H), 7.2-7.4 (m, 2H), 7.5 (m, 1H).

To a solution of piperidine (102 μL, 1.03 mmol) in toluene (620 μL) was added 2 M trimethylaluminum in toluene (620 μL), and the solution was stirred for 2 h. To the reaction mixture was added a solution of ethyl 3-[(1,1,1-trifluoro-2-hydroxypropyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzoate (100 mg, 0.21 mmol) in toluene (1 mL). The reaction mixture was heated at 40 ° C. for 20 h and 60° C. for 5 h, then cooled. To the reaction mixture was added water dropwise followed by 2 M hydrochloric acid and ethyl acetate. The solution was placed on a celite plug for 5 min, then eluted with dichloromethane, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 42.6 mg (38%) of the desired 1-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]-(3,3,3-trifluoro-2-hydroxypropyl)benzoyl]piperidine product as an orange oil. HRMS calcd. for C₂₄H₂₆F₇N₂O₃: 523.1832 [M+H]⁺, found: 523.1815. ¹H NMR (acetone-d₆) δ1.22-1.63 (m, 6H), 3.16-3.62 (m, 4H), 3.74 (dd, 1H), 4.00 (dd, 1H), 4.44-4.55 (m, 1H), 4.83 (s, 2H), 6.46 (tt, 1H), 6.64-6.69 (m, 2H), 6.83 (dd, 1H), 7.14-7.28 (m, 4H), 7.41 (t, 1H).

Additional examples of N,N-disubstituted-3-1(3,3,3-trifluoro-2-hydroxypropyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzamide are prepared by one skilled in the art using similar methods, as shown in Example Table 21.

Example Table 21. N,N-disubstituted-3-[(3,3,3-trifluoro-2-hydroxypropyl)]]3- (1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzamide

Calculated Obscrved Ex. Mass Mass No. R_(SUB) R′_(SUB) [M + H]⁺ [M + H]⁺ 457 H isopropyl 497.1675 497.1697 458 H n-butyl 511.1832 511.1809 459 H cyclohexyl 537.1988 537.1969 460 H tert-butyl 511.1832 511.1845 461 H cyclopentyl 523.1832 523.1854 462 H neo-pentyl 525.1988 525.2028 463 H 2,2,2-trifluoroethyl 537.1236 537.1250 464 H 2,2,3,3,4,4,4- 637.1172 637.1177 heptafluorobutyl 465 H phenylmethyl 545.1675 545.1705 466 H (3-trifluoromethoxy)- 629.1498 629.1510 phenylmethyl 467 H 4-(fluorophenyl)methyl 563.1581 563.1611 468 methyl phenyl 545.1675 545.1631 469 methyl phenylmethyl 559.1832 559.1853 470 —CH₂CH₂N(CH₃)CH₂CH₂— 538.1941 538.1969 471 —CH₂CH₂OCH₂CH₂— 525.1624 525.1615 472 —CH₂CH₂CH₂CH₂— 509.1675 509.1675

EXAMPLE 473

3-[[3-[(1-methylethyl)thiolphenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

EX-473A) 3-Aminobenzenethiol (2.4 mL, 22.5 mmol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (5 g, 22.5 mmol) were dissolved in 40 mL of dichloroethane and acetic acid (1.35 mL, 23.7 mmol), then solid NaBH(OAc)₃ (6.2 g, 29.3 mmol) was added. The mixture was stirred at room temperature for 18 hours, then quenched with water and diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate, then dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give 5.36 g (72%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzenethiol product as a brown oil. ¹H NMR (CDCl₃) δ3.4 (s, 1H), 4.4 (s, 2H), 5.9 (tt, 1H), 6.4 (dd, 1H), 6.55 (m, 1H), 6.65 (d, 1H), 7.05 (t, 1H), 7.2-7.4 (m, 4H).

EX-473B) The EX-473A benzenethiol amine (5.36 g, 16.2 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (1 g, 1.6 mmol) were dissolved in 20 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (1 g, 1.6 mmol) was added, and the stirred solution was warmed to 50° C. for 48 hours, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, then dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give 4.5 g (63%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzenethiol product as a yellow oil. ¹H NMR (CDCl₃) δ3.0 (s, 1H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.2 (m, 1H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.5 (dd, 1H), 6.7 (m, 2H), 7.1 (m, 4H), 7.4 (t, 1H). HRMS calcd. for C₃₆H₃₁F₁₄N₂O₄S₂: 885.1502 [2(M−1)+H]⁺, found: 885.1471.

The EX-473B thiol product (150 mg, 0.34 mmol) and 2-iodopropane (37 μL, 0.37 mmol) were dissolved in 2 mL of acetonitrile. Cesium carbonate (144 mg, 0.44 mmol) was added, and the stirred solution was warmed to 55° C. for 18 hours, at which time HPLC analysis indicated that no thiol/disulfide starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 69 mg (42%) of the desired 3-[[3-[(1-methylethyl)thio]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₁H₂₃F₇NO₂S: 486.1338 [M+H]⁺, found: 486.1351. ¹H NMR (CDCl₃) δ1.2 (t, 3H), 3.3 (q, 1H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.7 (m, 3H), 5.9 (tt, 1H), 6.7 (dd, 1H), 6.9 (m, 2H), 7.0-7.2 (m, 4H), 7.3 (t, 1H).

Additional examples of 3-[[3-(alkanoyl-, aryl-, heteroaryl-, and aralkylthio) phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 22.

Example Table 22 3-[[3-(alkanoyl-, aryl-, heteroaryl-, and aralkylthio)phenyl][[3-(1,1,2,2-tetrafluoro- ethoxy)phenyl]methyl]amino]-1,1,1- trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 474 4-pyridyl 521.1134 521.1115 475 4-nitrophenyl 565.1032 565.1034 476 4-piperidyl 527.1603 527.1597 477 2-pyridylmethyl 535.1290 535.1291 478 4-acetylphenyl 562.1287 562.1261 479 4-(methylsulfonyl)phenyl 598.0957 598.0946 480 (4-chloro-thien-2-yl)methyl 574.0512 574.0523 481 acetyl 486.0974 486.0936

EXAMPLE 482

3-[[3-[(1-methylethyl)sulfonyl]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of 3-[[3-[(1-methylethyl)thio]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (58 mg, 0.12 mmol) in 2 mL of trifluoroacetic acid, was added 30% aqueous H₂O₂ (28 μL, 0.25 mmol). The mixture was stirred at room temperature for 18 hours, then quenched with 5% aqueous sodium hydroxide and extracted with ether. The organic layer was concentrated in vacuo. The crude product was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 29.5 mg (48%) of the desired sulfone product as a brown oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₁H₂₃F₇NO₄S: 518.1236 [M+H]⁺, found: 518.1226. ¹H NMR (CDCl₃) δ1.1 (d, 6H), 3 (q, 1H), 3.7 (dd, 1H), 3.9 (dd, 1H), 4.3 (m,1H), 4.7 (s, 1H), 5.9 (tt, 1H), 7 (m, 2H), 7.1-7.2 (m, 4H), 7.3 (m, 2H).

Additional examples of 3-[(3-(aryl-, heteroaralkyl-, and heterocyclyl-sulfonyl)phenyl][[3-(1,1,2,2-tetra-fluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 23.

Example Table 23. 3-[(3-(aryl-, heteroaralkyl-, and heterocyclyl- sulfonyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]- 1,1,1-trifluoro-2-propanols.

Calculated Ex. Mass Observed Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 483 4-nitrophenyl 597.0930 597.0925 484 4-piperidyl 559.1502 559.1526 485 3-(pyridyl-N-oxide)methyl 583.1138 583.1137 486 4-acetylphenyl 594.1185 594.1181 487 4-(methylsulfonyl)phenyl 630.0855 630.0826

EXAMPLE 488

3-[[3-(cyclohexylmethoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](1,1,1-trifluoro-2-hydroxy-propyl)-amino]phenol (100 mg, 0.23 mmol) and bromomethylcyclohexane (42 μL, 0.30 mmol) were dissolved in 2 mL of acetonitrile. Cesium carbonate (144 mg, 0.44 mmol) was added, and the stirred solution was warmed to 50° C. for 48 hours, at which time HPLC analysis indicated that no phenolic starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 55 mg (35%) of the desired ether product as a brown oil, which was greater than 99% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₅H₂₉F₇NO₃: 524.2036 [M+H]⁺, found: 524.2028. ¹H NMR (CDCl₃) δ0.9-1.4 (m, 5H), 1.7-1.9 (m, 6H), 3.6 (m, 3H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.7 (m, 2H), 5.1 (s, 1H), 5.9 (tt, 1H), 6.5 (m, 3H), 7.0-7.4 (m, 5H).

Additional examples of 3-[(3-alkoxy- and cycloalkoxy-phenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 24.

Example Table 24. 3-[(3-alkoxy- and cycloalkoxy-phenyl)]]3-(1,1,2,2- tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 489 isopropyl 470.1488 470.1565 490 (methoxycarbonyl)methyl 500.1308 500.1297 491 cyanomethyl 467.1206 467.1228 492 2-methylpropyl 484.1723 484.17l8 493 2-oxobutyl 498.1515 498 1529 494 cyclohexyl 510.1880 510.1910 495 5-oxohexyl 526.1828 526.1827 496 4-(methoxycarbonyl)butyl 542.1777 542.1827 497 2-(phenylsulphonyl)ethyl 596.1342 596.1349 498 2-pyrrolidinylethyl 525.1988 525.2008 499 3-(methoxycarbonyl)-2-propenyl 526.1464 526.1482 500 carbamoylmethyl 485.1311 485.1304 501 3-cyanopropyl 495.1519 495.1541 502 1-(N-phenylcarbamoyl)ethyl 575.1780 575.1778 503 2-oxo-2-phenylethyl 546.1515 546.1543 504 3-hydroxypropyl 486.1515 484.1481 505 2-methoxyethyl 486.1515 486.1537 506 neo-pentyl 498.1879 498.1845 507 4-tetrahydropyranyl 512.1672 512.1631 508 1-ethoxycarbonylbutyl 556.1934 556.1948 509 cyclopentyl 496.1723 496.1719 510 3-methyl-2-butenyl 496.1722 496.1675 511 2-(N,N-dimethylamino)ethyl 499.1831 499.1826 512 3-hydroxy-2,2-dimethylpropyl 514.1828 514.1814 513 3,3-dimethyl-2-oxobutyl 526.1828 526.1806

EXAMPLE 514

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[(3-trifluoromethyl)-phenyl]methyl]phenyl]amino]-1,1,1-trifluoro-2-propanol

EX-514A) To a solution of (3-nitrobenzene)methanol (10 g, 65.3 mmol) in 50 mL of 5% aqueous sodium hydroxide, was added dimethylsulfate (20 g, 156 mmol). The mixture was stirred at 70° C. for 18 hours, then diluted with water and ethyl acetate. The organic layer was washed with water, then dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:5 to give 4.73 g (43%) of the desired 3-(methoxy-methyl)nitrobenzene product as a yellow oil. ¹H NMR (CDCl₃) δ3.5 (s, 3H), 4.5 (s, 2H), 6.5 (t, 1H), 7.7 (d, 1H), 8.1 (d, 1H), 8.2 (s, 1H).

EX-514B) The 3-(methoxymethyl)nitrobenzene (4.18 g, 25 mmol) from EX-514A was dissolved in 160 mL of acetic acid. Zinc dust (5 g, 76.5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no 3-(methoxymethyl)nitrobenzene starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with water, then dried over MgSO₄, and concentrated in vacuo to give 3.4 g (99%) of the desired 3-methoxymethyl)aniline as a brown oil. The crude product was used without further purification. HRMS calcd. for C₈H₁₂NO: 138.0919 [M+H]⁺, found: 138.0929. ¹H NMR (CDCl₃) δ3.4 (s, 3H), 3.7 (s, 2H), 4.4 (s, 2H), 6.6 (d, 1H), 6.7 (m, 2H), 7.2 (t, 1H).

EX-514C) The 3-(methoxymethyl)aniline (1.85 g, 13.51 mmol) product from EX-514B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (3 g, 13.5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.8 mmol), then solid NaBH(OAc)₃ (3.73 g, 17.6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO₄, and concentrated in vacuo to give 4.27 g (12.4 mmol) of crude product. The crude product and 1,1,1-trifluoro-2,3-epoxypropane (1.2 mL, 13.7 mmol) were dissolved in 20 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.77 g, 1.24 mmol) was added, and the stirred solution was warmed to 50° C. for 18 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO₄, and concentrated in vacuo to give 5.96 g (97%) of the desired 3-[[3-(methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. The crude product was greater than 95% pure by reverse phase HPLC analysis and was used without further purification. HRMS calcd. for C₂₀H₂₁F₇NO₃: 456.1410 [M+H]⁺, found: 456.1409. ¹H NMR (CDCl₃) δ3.3 (s, 3H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.4 (s, 2H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.6-6.8 (m, 3H), 7.1-7.2 (m, 4H), 7.3 (t, 1H).

EX-514D) The 3-[[3-(methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol from EX-514C (1 g, 2.2 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to −50° C. and a 1 M solution of BBr₃ in dichloromethane (2.3 mL, 2.3 mmol) was added. The solution was stirred at −50° C. for 1 hour and warmed to room temperature over 1 hour, at which time HPLC analysis indicated that no methyl ether starting material remained. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted in dichloromethane. The organic layer was washed with brine, then dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 0.65 g (59%) of the desired 3-[[3-(bromomethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C₁₉H₁₈BrF₇NO₂: 504.0409 [M+H]⁺, found: 504.0361. ¹H NMR (CDCl₃) δ3.3 (s, 1H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.4 (s, 2H), 4.8 (m, 2H), 5.9 (tt, 1H), 6.7 (d, 1H), 6.8-6.9 (m, 2H), 7.1-7.3 (m, 4H), 7.4 (t, 1H).

The 3-[[3-(bromomethyl)phenyl][[3-(1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol from EX-514D (0.1 g, 0.19 mmol) and 3-trifluoromethyl-benzeneboronic acid (47.5 mg, 0.25 mmol) were dissolved in 2 mL of toluene and 0.2 mL of 2 M aqueous sodium carbonate. Pd(PPh₃)₄ was added, and the solution was stirred at 105° C. for 2.5 hours, at which time HPLC analysis indicated that no bromomethyl starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16.7 mg (15%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-[3-[(3-trifluoromethyl)phenyl]methyl]phenyl]-amino]-1,1,1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C₂₆H₂₂F₁₀NO₂: 570.1413 [M+H]⁺, found: 570.1480. ¹H NMR (CDCl₃) δ3.8 (m, 2H), 4.0 (s, 2H), 4.3 (m, 1H), 4.5 (d, 1H), 4.8 (d, 1H), 5.9 (tt, 1H), 6.6-6.8 (m, 4H), 6.9-7.1 (m, 3H), 7.2-7.5 (m, 5H).

Additional examples of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(aryl)methyl]phenylamino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 25.

Example Table 25. 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]- [3-(aryl)methyl]phenylamino]-1,1,1-trifluor-2-propanols.

Example Calculated Observed Mass Number R_(SUB) Mass [M + H]⁺ [M + H]⁺ 515 H 502.1617 502.1609 516 3-nitro 547.1468 547.1449 517 4-methyl 516.1774 516.1769 518 3,5-dichloro 570.0838 570.0801 519 4-fluoro 520.1523 520.1505 520 4-tert-butyl 558.2243 558.2236 521 3-methyl-4-fluoro 534.1679 534.1688 522 3-methyl-4-chloro 550.1384 550.1380 523 3,4-dimethyl 530.1930 530.1887 524 3-chloro,4-fluoro 554.1133 554.1108 525 3-chloro 536.1227 536.1218 526 4-methylthio 548.1494 548.1503 527 3-methoxy 532.1723 532.1705

EXAMPLE 528

4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzenesulfonamide

EX-528A) 3-nitroaniline (1.87 g, 13.51 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (3 g, 13.5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.9 mmol), then solid NaBH(OAc)₃ (3.73 g, 17.6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 3.25 g (70%) of the desired N-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethan-amine product as a brown oil. HRMS calcd. for C₁₅H₁₃F₄N₂O₃: 345.0862 [M+H]⁺, found: 345.0864. ¹H NMR (CDCl₃) δ4.4 (s, 2H), 4.5 (s, 1H), 5.9 (tt, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 2H), 7.5 (d, 1H).

EX-528B) N-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy)benzene-methanamine (3.25 g, 9.44 mmol) from EX-528A and 1,1,1-trifluoro-2,3-epoxypropane (0.895 mL, 10.4 mmol) were dissolved in 15 mL of acetonitrile. Ytterbium (III) trifluoromethane-sulfonate (0.77 g, 1.24 mmol) was added, and the stirred solution was warmed to 55° C. for 48 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give 1.93 g (45%) of the desired 3-[(3-nitrophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C₁₈H₁₆F₇N₂O₄: 457.0998 [M+H]⁺, found: 457.1008. ¹H NMR(CDCl₃)δ3.7 (dd, 1H), 3.9 (dd, 1H), 4.4 (m, 1H), 4.8 (m, 2H), 5.9 (tt, 1H), 7.0-7.2 (m, 4H), 7.3-7.4 (m, 2H), 7.6 (m, 2H).

EX-528C) The 3-[(3-nitrophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (1.93 g, 4.2 mmol) from EX-528B) was dissolved in 60 mL of acetic acid. Zinc dust (2.1 g, 31.5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no nitro starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with brine, then dried over MgSO₄, and concentrated in vacuo to give 1.4 g (78%) of the desired 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a red oil. The crude product was used without further purification. HRMS calcd. for C₁₈H₁₈F₇N₂O₂: 427.1256 [M+H]⁺, found: 427.1251. ¹H NMR (CDCl₃) δ3.4-3.7 (m, 4H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.8 (m, 2H), 5.9 (tt, 1H), 6.1 (s, 1H), 6.2 (m, 2H), 7.0-7.2 (m, 4H), 7.3 (t, 1H).

The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol from EX-528C (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzene-sulfonyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no free amine starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 20.1 mg (29%) of the desired 4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzenesulfonamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₄H₂₁F₈N₂O₄S: 585.1094 [M+H]⁺, found: 585.1083. ¹H NMR (CDCl₃) δ3.6 (m, 2H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.4 (d, 1H), 6.5-6.6 (m, 3H), 6.9-7.4 (m, 7H), 7.6 (m, 1H).

Additional examples of N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,-trifluoro-2-hydroxypropyl)amino]phenyl]aryl or alkylsulfonamide are prepared by one skilled in the art using similar methods, as shown in Example Table 26.

Example Table 26. N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3- trifluoro-2-hydroxypropyl)amino]phenyl]aryl or alkylsulfonamides.

Calculated Observed Example Mass Mass Number R_(SUB) [M + H]⁺ [M + H]⁺ 529 phenyl 567.1189 567.1198 530 3-methylphenyl 581.1345 581.1327 531 3-trifluoromethylphenyl 635.1062 635.1066 532 3-nitrophenyl 612.1039 612.1011 533 3-chloro-4-fluorophenyl 619.0705 619.0711 534 isopropyl 533.1345 533.1359

EXAMPLE 535

4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzamide

3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzoyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 15 mg (23%) of the desired 4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]-phenyl]benzamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₅H₂₁F₈N₂O₃: 549.1424 [M+H]⁺, found: 549.1436. ¹H NMR (CDCl₃) δ3.6 (dd, 1H), 3.8 (dd, 1H), 4.4 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.8 (d,1H), 7.0-7.4 (m, 7H), 7.8 (m, 3H).

Additional examples of N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]carboxamides are prepared by one skilled in the art using similar methods, as shown in Example Table 27.

Example Table 27. N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]- (3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]carboxamides.

Example Calculated Observed Number R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 536 phenyl 531.1589 531.1538 537 3-methoxylphenyl 561.1624 561.1625 538 isobutoxy 527.1781 527.1768 539 3-pyridyl 532.1471 532.1458 540 isopropyl 497.1675 497.1701

EXAMPLE 541

3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

The 3-[(3-aminophenyl )[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloroethane. Acetic acid (8 μL, 0.14 mmol) followed by isobutyraldehyde (11.7 μL, 0.13 mmol) and solid NaBH(OAc)₃ (37.3 mg, 0.18 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16.1 mg (29%) of the desired 3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₂H₂₆F₇N₂O₂: 483.1883 [M+H]⁺, found: 483.1932. ¹H NMR (CDCl₃) δ1.0 (m, 6H), 2.0 (m, 1H), 3.0 (m, 2H), 3.6 (dd, 1H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.9-7.4 (m, 6H).

Additional examples of 3-[[3-(aralkylamino)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 28.

Example Table 28. 1,1,1-trifluoro-3-[[3-(aralkylamino)phenyl]-[[3-(1,1,2,2- tetrafluoroethoxy)phenyl]methyl]amino]-2-propanols.

Example Calculated Observed Number R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 542 phenyl 517.1726 517.1750 543 4-fluorophenyl 535.1632 535.1627 544 3-(OCF₂CF₂H)-phenyl 633.1611 633.1653

EXAMPLE 545

N-(4-fluorophenyl)-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]urea

The 3[-(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (20 μL, 0.14 mmol) followed by 4fluorophenyl isocyanate (14.6 μL, 0.13 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 26 mg (40%) of the desired N-(4-fluorophenyl)-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]urea product as a yellow oil, which was greater than 95% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₅H₂₂F₈N₃O₃: 564.1533 [M+H]⁺, found: 564.1566. ¹H NMR(CDCl₃) δ3.7 (m, 2H), 4.1 (m, 1H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.9-7.4 (m, 11H), 7.5 (s, 1H), 7.8 (s, 1H).

Additional examples of N-substituted-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methy](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]ureas are prepared by one skilled in the art using similar methods, as shown in Example Table 29.

Example Table 29. N-substituted-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]- methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]ureas.

Example Calculated Observed Number R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 546 phenyl 546.1628 546.1655 547 3-methoxyphenyl 576.1733 576.1773 548 3-trifluoromethylphenyl 614.1501 614.1518 549 isopropyl 512.1784 512.1801

EXAMPLE 550

1,1,1-trifluoro-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][[3′-(trifluoromethyl)1,1′-biphenyl]-3-yl]amino]-2-propanol

3-Trifluomethylbenzene boronic acid (35.4 mg, 0.233 mmol) was dissolved in 640 mL of 2 M Na₂CO₃, and 630 mL of ethanol then 1.5 mL of a stock solution of 3[-(3-bromophenyl )[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]1,1,1-trifluoro-2-propanol (0.105 M) and 10.9 mg/mL of Pd(PPh₃)₄ in toluene was added. After stirring at 105° C. for 5 hours, HPLC analysis indicated that the reaction had gone to completion. The reaction mixture was filtered through celite, evaporated, and the crude material purified by reverse phase HPLC eluting with 40% to 90% acetonitrile in water to afford 40.5 mg (44.7%) of the desired biphenyl aminopropanol product as an orange oil. HRMS calcd. for C₂₅H₁₉F₁₀NO₂: 556.1334 [M+H]⁺, found: 556.1339. ¹H NMR (CDCl₃) δ3.60-3.73 (m, 1H), 3.95 (dd, 1H), 4.36-4.44 (m, 1H), 4.76 (s, 2H), 5.87 (tt, 1H), 6.81 (dd, 1H), 6.95 (s, 1H), 7.03 (d, 1H), 7.05-7.20 (m, 3H), 7.26-7.40 (m, 2H), 7.46-7.73 (m, 4H).

Additional examples of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][[3-aryl]phenyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 30.

Example Table 30. 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][[3- aryl]phenyl]amino]-1,1,1-trifluoro-2-propanols.

Example Calculated Observed Number R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 551 3,5-di(trifluoromethyl) 624.1208 624.1216 552 4-trifluoromethyl 556.1334 556.1355 553 4-methylthio 534.1337 534.1366 554 3-chloro-4-fluoro 540.0976 540.0957 555 3,5-dichloro-4-methoxy 586.0786 586.0818 556 3-nitro 533.1311 533.1262 557 3,5-dichloro 556.0681 556.0612 558 4-methoxy 518.1566 518.1533 559 3,4-difluoro 524.1272 524.1249 560 2,3,4-trifluoro 542.1177 542.1152 561 3,4-dichloro 556.0681 556.0698 562 3-methyl-4-methoxy 532.1722 532.1676 563 3,5-dimethyl-4-(N,N- 559.2195 559.2182 dimethylamino) 564 H 488.1460 488.1457 565 4-chloro 522.1071 522.1049 566 4-methyl 502.1617 502.1613 567 2,4-dichloro 556.0681 556.0651 568 4-fluoro 556.1366 506.1336 569 4-fluoro-3-methyl 520.1523 520.1494 570 2-trifluoromethyl 556.1334 556.1286 571 3-methoxy 518.1566 518.1544 572 3-amino 503.1569 503.1593 573 4-carboxy 532.1358 532.1329 574 4-tert-butyl 544.2087 544.2090

EXAMPLE 575

3-[[[4′-(methylsulfonyl)1,1′-biphenyl]-3-yl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][[4-(methylthio)-phenyl]phenyl]amino]-1,1,1-trifluoro-2-propanol in 2 mL of trifluoroacetic acid was added 11 mL of 30% H₂O₂ (0.097 mmol). After stirring at room temperature overnight, an additional 11 mL of 30% H₂O₂ (0.097 mmol) was added. After 5 hours, TLC analysis indicated that the reaction had gone to completion. The solvent was removed, and the residue was filtered through silica gel eluting with 30% ethyl acetate in hexane. The material was evaporated to give 36.6 mg (100%) of the desired sulfone product as an oil which was 100% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₅H₂₂F₇NO₄S: 566.1236 [M+H]⁺, found: 566.1193. ¹H NMR (CDCl₃) δ3.04 (s, 3H), 3.66-3.79 (m, 1H), 3.97 (d, 1H), 4.35-4.43 (m, 1H), 4.69-4.81 (m, 2H), 5.86 (dt, 1H), 6.90 (d, 1H), 7.01 (s, 1H), 7.05-7.18 (m, 4H), 7.31-7.40 (m, 2H), 7.60 (d, 2H), 7.93 (d, 2H).

EXAMPLE 576

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile

EX-576A) A solution of 3-aminobenzonitrile (1.06 g, 9.1 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (2.00 g, 9.01 mmol) was dissolved in 25 mL of dichloroethane and acetic acid (536 mL, 9.37 mmol), then solid NaBH(OAc)₃ (2.48 g, 11.7 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃, then dried over MgSO₄, and evaporated. The crude product was purified by MPLC on silica gel eluting with 20% to 30% ethyl acetate in hexane to give 1.58 g (54%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]benzonitrile product as a clear oil. ¹H NMR (CDCl₃) δ4.38 (s, 3H), 5.89 (dt, 1H), 6.79 (t, 1H), 6.98 (d, 2H), 7.12-7.28 (m, 4H), 7.40 (t, 1H).

The benzonitrile (1.58 g, 4.88 mmol) from EX-576A and 1,1,1-trifluoro-2,3-epoxy-propane (546 mL, 6.34 mmol) were dissolved in 4 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (304 mg, 0.49 mmol) was added, and the stirred solution was warmed to 50° C. overnight. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, dried over MgSO₄ and evaporated. The crude product was purified by MPLC on silica gel eluting with dichloromethane to give 1.61 g (76%) of the desired 3-[[[1,1,2,2-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile product as a clear oil, greater than 98% by reverse phase HPLC. HRMS calcd. for C₁₉H₁₅F₇N₂O₂: 437.1100 [M+H]⁺, found: 437,1097. ¹H NMR (CDCl₃) δ3.60-3.69 (m, 1H), 3.86 (d, 1H), 4.32 (bs, 1H), 4.69 (q, 2H), 5.86 (dt, 1H), 6.85-6.95 (m, 2H), 6.97-7.01 (m, 2H), 7.04-7.12 (m, 2H), 7.23-7.37 (m, 2H).

EXAMPLE 577

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(1H-tetrazol-5-yl)phenyl]amino]-1,1,1-trifluoro-2-propanol

To a solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile (76 mg, 0.17 mmol) in 2 mL of toluene was added trimethyltin azide (41 mg, 0.20 mmol). The reaction mixture was heated to 105° C. and stirred overnight. TLC showed starting material to still be present so additional trimethyltin azide (41 mg, 0.20 mmol) was added. The reaction mixture was stirred overnight at 105° C., cooled to room temperature, then THF (800 μL) and concentrated HCl (500 μL) were added. HPLC analysis showed 2 peaks after 5 hours, so additional concentrated HCl (200 μL) was added. After stirring overnight, HPLC analysis showed the reaction to be complete. The mixture was filtered through a celite plug and evaporated in vacuo. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 27.2 mg (33%) of the desired tetrazole product as an oil. HRMS calcd. for C₁₉H₁₆F₇N₅O₂: 480.1270 [M+H]⁺, found: 480.1252. ¹H NMR (CDCl₃) δ3.66-3.99 (m, 2H), 4.45-4.75 (m, 3H), 5.80 (dt, 1H), 6.49-6.70 (m, 1H), 6.95 (s, 1H), 6.97-7.06 (m, 3H), 7.18-7.28 (m, 3H), 7.34 (s, 1H).

EXAMPLE 578

(4-Fluoro-3-methylphenyl)[3-[[[(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]methanone

To a solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile (100 mg, 0.23 mmol) in 1 mL of anhydrous THF under nitrogen was added 4fluoro-3-methylphenylmagnesium bromide (0.81 mL of 1.0 M solution, 0.81 mmol), and the mixture was stirred at room temperature overnight. HPLC analysis of the reaction mixture showed the presence of starting material so additional 4fluoro-3-methylphenylmagnesium bromide (0.46 mL. 0.41 mmol) was added. HPLC analysis 24 hours later showed the reaction to be complete. The reaction was quenched and acidified with 1 N HCl. After hydrolysis of imine was complete by HPLC analysis, the mixture was filtered through celite and evaporated. The crude product was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 28.0 mg (22%) of the desired ketone product as an oil. HRMS calcd. for C₂₆H₂₁F₈NO₃: 548.1410 [M+H]⁺, found: 548.1441. ¹H NMR (CDCl₃) δ2.26 (s, 3H), 3.60-3.70 (m, 1H), 3.92 (d, 1H), 4.26-4.40 (m, 1H), 4.68 (t, 2H), 5.87 (dt, 1H), 6.91-7.03 (m, 3H), 7.05-7.12 (m, 4H), 7.26-7.35 (m, 2H), 7.43-7.52 (m, 1H), 7.63 (d, 1H).

Additional examples of (aryl-, alkyl- or cycloalkyl-)[3-[[[(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]methanones are prepared by one skilled in the are using similar methods, as shown in Example Table 31.

Example Table 31. (Aryl-, alkyl- or cycloalkyl-)[3-[[[(1,1,2,2- tetrafluoroethoxy)-phenyl]methyl](3,3,3-trifluoro-2- hydroxypropyl)amino]phenyl]methanones.

Example Calculated Observed Number R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 579 phenyl 516.1410 516.1383 580 4-fluorophenyl 534.1315 534.1273 581 cyclopentyl 508.1723 508.1675 582 isopropyl 482.1566 482.1576

EXAMPLE 583

α-Phenyl-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]](3,3,3-trifluoro-2-hydroxypropyl)benzenemethanol

To a solution of phenyl[3-[[[(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]methanone (155.8 mg, 0.302 mmol) in 2.3 mL of methanol cooled to 5° C. was added solid NaBH₄ (34.5 mg, 0.912 mmol). HPLC analysis after 1 hour showed no ketone starting material. The reaction was evaporated to dryness and purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to give 35.6 mg (24%) of the desired alcohol product as an oil. HRMS calcd. for C₂₅H₂₂F₇NO₃: 518.1566 [M+H]⁺, found: 518.1563. ¹H NMR (acetone-d₆) δ3.56-3.73 (m, 1H), 3.92-4.06 (m, 1H), 4.40-4.55 (m, 1H), 4.82 (s, 2H), 5.71 (s, 1H), 6.28-6.69 (m, 2H), 6.71-6.82 (m, 1H), 6.93 (s, 1H), 7.07-7.51 (m, 10H).

Additional examples of α-alkyl-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][(3,3,3-trifluoro-2-hydroxypropyl)benzenemethanols are prepared by one skilled in the art using similar methods, as shown in Example Table 32.

Example Table 32. α-alkyl-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]- [(3,3,3-trifluoro-2-hydroxypropyl)benzenemethanols

Example Calculated Observed Number R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 584 isopropyl 484.1723 484.1725

EXAMPLE 585

Ethyl 3-[(3,3,3-trifluoro-2-hydroxypropyl)[[(3-trifluoromethoxy)phenyl]methyl]amino]benzoate

EX-585A) Ethyl 3-aminobenzoate (3.9 mL, 26 mmol) and 3-trifluoromethoxybenzaldehyde (4.91 g, 25.8 mmol) were dissolved in 65 mL of dichloroethane and acetic acid (1.6 mL, 28 mmol), then solid NaBH(OAc)₃ (7.5 g, 34.2 mmol) was added. The mixture was stirred at room temperature overnight, then quenched with water and extracted with dichloromethane. The organic layer was washed with brine, then dried over MgSO₄, and evaporated to give 9.76 g (>100%) of the desired ethyl 3-[[[(3-trifluoromethyl)phenyl]methyl]amino]benzoate product as a yellow oil, which was greater than 95% pure by reverse phase HPLC analysis. ¹H NMR (CDCl₃) δ1.35 (t, 3H), 4.26-4.41 (m, 5H), 6.73 (d, 1H), 7.12 (d, 1H), 7.15-7.25 (m, 2H), 7.25-7.43 (m, 4H).

The ethyl 3-[[[(3-trifluoromethyl)phenyl]methyl]amino]benzoate (9.76 g, 25.8 mmol) product from EX-585A and 1,1,1-trifluoro-2,3-epoxypropane (2.9 mL, 33.5 mmol) were dissolved in 25 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (1.6 g, 2.6 mmol) was added, and the stirred solution was warmed to 50° C. for 20 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water and brine, then dried over MgSO₄. The crude product was purified by column chromatography on silica gel eluting with dichloromethane to give 10.7 g (92%) of the desired ethyl 3-(3,3,3-trifluoro-2-hydroxypropyl)[[(3-trifluoromethyl)phenyl]methyl]amino]benzoate product as a yellow oil. HRMS calcd. for C₂₀H₁₉NO₄F₆. 452.1297 [M+H]⁺, found: 452.1256. ¹H NMR (CDCl₃) δ1.32 (t, 3H). 2.94-3.02 (m, 1H), 3.54-3.64 (m, 1H), 3.91 (d, 1H), 4.24-4.40 (m, 3H), 4.69 (t, 2H), 6.86 (d, 1H), 7.05 (s, 1H), 7.07-7.14 (m, 2H), 7.20-7.34 (m, 2H), 7.39-7.47 (m, 2H).

EXAMPLE 586

3-[(3,3,3-trifluoro-2-hydroxypropyl)[[(3-trifluoromethyl)phenyl]methyl]amino]benizoic Acid

Ethyl 3-[(3,3,3-trifluoro-2-hydroxypropyl )[[(3-trifluoromethyl)phenyl]methyl]amino]-benzoate was dissolved in 70 mL of THF and 35 mL of water. Lithium hydroxide monohydrate (2.93 g, 69.8 mmol) was added, and the mixture was heated to 45° C. under nitrogen overnight, at which time HPLC analysis indicated that the reaction had gone to completion. The mixture was acidified with 1 N HCl to a pH of 3-4, then extracted with ethyl acetate several times, and the combined organic layers were dried over MgSO₄. The dried organic layer was evaporated to give 11.2 g (100%) of the desired benzoic acid product as a pale orange oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C₁₈H₁₅NO₄F₆. 424.0984 [M+H]⁺, found: 424.0991. ¹H NMR (acetone-d₆) δ3.68-3.81 (m, 1H), 3.99-4.09 (m, 1H), 4.43-4.58 (m, 1H), 4.87 (s, 2H), 7.02 (d, 1H), 7.19 (d, 1H), 7.22-7.40 (m, 4H), 7.40-7.49 (m, 2H).

EXAMPLE 587

3-[(3-phenoxyphenyl)[[3-(2-pyridinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-587A) To a THF solution (8 mL) of 2-bromopyridine (1.30 g, 8.23 mmol) at −78° C. was added 1.6 M n-BuLi in hexanes (5.3 mL, 8.48 mmol). The resulting dark red solution was stirred at −78° C. for 10 min, and a solution of 0.5 M ZnCl₂ in THF (18 mL, 9.0 mmol) was added giving a light brown slurry. After warming to room temperature, 3-bromobenzaldehyde (0.816 mL, 7.0 mmol) and Pd(PPh₃)₄ (0.242 g, 0.21 mmol) were added, and the mixture was stirred for 18 h at room temperature under argon. The reaction mixture was poured into 1 N HCl (30 mL) and washed with diethyl ether. The aqueous layer was neutralized with NaHCO₃ and extracted with diethyl ether. The solvent was removed in vacuo to give the crude product as an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.49 g (38%) of the desired 3-(2-pyridinyl)benzaldehyde product as a colorless oil. GCMS: m/z=183 [M⁺].

EX-587B) To a 1,2-dichloroethane (5 mL) solution of aldehyde (0.37 g, 2.0 mmol) from EX-587A was added 3-phenoxyaniline (0.37 g, 2.0 mmol), NaB(OAc)₃H (0.55 g, 2.6 mmol) and acetic acid (0.12 mL, 2.0 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 0.70 g (100%) of the desired N-3-(phenoxyphenyl)-[[3-(2-pyridinyl)phenyl]methyl]amine product as a yellow oil. HRMS: calcd. for C₂₄H₂₁N₂O: 353.1654 [M+H]⁺, found: 353.1660.

A THF (1 mL) solution of amine (0.47 g, 1.3 mmol) from EX-587B and 1,1,1-trifluoro-2,3-epoxypropane (0.35 mL, 4.1 mmol) was placed in a sealed vial and heated to 90° C. for 18 h with stirring. The solvent was removed in vacuo to give the crude product as an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.026 g (4.2%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-pyridinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil. HRMS calcd. for C₂₇H₂₄N₂O₂F₃: 465.1790 [M+H]⁺, found: 465.1798. ¹H NMR (CDCl₃) δ3.63 (dd, 1H), 3.73 (br s, 1H), 3.82 (dd, 1H). 4.30 (m, 1H), 4.67 (d, 2H), 6.34 (dd, 1H), 6.44 (t, 1H), 6.52 (dd, 1H), 6.92 (d, 2H), 7.02 (t, 1H), 7.12 (t, 1H), 7.2 (m, 4H), 7.38 (t, 1H), 7.65 (d, 1H), 7.72 (d, 1H), 7.74 (d1H), 7.84 (s, 1H), 8.62 (d, 1H).

EXAMPLE 588

3-[(3-phenoxyphenyl)[[3-[(3-trifluoromethyl)-2-pyridinyl]phenyl]methyl]amino],-1,1,1-trifluoro-2-propanol

EX-588A) To a toluene (10 mL) solution of 2-bromo-3-trifluoromethylpyridine (1.10 g, 4.87 mmol) was added 3-formylphenylboronic acid (0.90 g, 6.0 mmol) and DMF (4 mL). To the resulting solution was added K₂CO₃ (1.67 g, 12.1 mmol) and Pd(PPh₃)₄ (0.35 g, 0.30 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.55 g (45%) of the desired 3-[(3-trifluoromethyl)-2-pyridinyl]benzaldehyde product as a color-less oil which solidified upon standing. HRMS: calcd. for C₁₃H₉NOF₃: 252.0636 [M+H]⁺, found: 252.0639.

EX-588B) A mixture of solid 3-phenoxyaniline (2.96 g, 16 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (1.30 mL, 15.0 mmol) was placed in a sealed tube and heated to 100° C. giving a dark solution. The stirred solution was heated 18 h and cooled to give a dark oil. Purification by flash chromatography on silica gel eluting with dichloromethane gave 3.15 g (71%) of the desired 3-[(N-3-phenoxy-phenyl)amino]1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C₁₅H₁₄NO₂F₃.0.05 CH₂Cl₂: C, 59.92; H, 4.71; N, 4.64. Found: C. 59.92; H, 4.53; N, 4.73. ¹HRMS calcd. 298.1055 [M+H]⁺, found: 298.1056.

To a 1,2-dichloroethane (8 mL) solution of aldehyde (0.55 g, 2.2 mmol) from EX-588A was added the amine (0.66 g, 2.2 mmol) from EX-588B, NaB(OAc)₃H (0.61 g, 2.9 mmol) and acetic acid (0.15 mL, 2.6 mmol). The cloudy solution was stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to give an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.33 g (29%) of the desired 3[-(3-phenoxyphenyl)[[3-[(3-trifluoromethyl )-2-pyridinyl]phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a white foam, >97% pure by HPLC analysis. Anal. calcd. for C₂₈H₂₂N₂F₆: C, 63.16; H, 4.16; N, 5.26. Found: C, 62.87; H, 4.02; N, 5.33. HRMS: calcd. 533.1664 [M+H]⁺, found: 533.1658. ¹H NMR (C₆D₆) δ2.97 (d, 1H), 3.26 (dd, 1H), 3.46 (dd, 1H), 3.77 (m, 1H), 4.22 (dd, 2H), 6.31 (dd, 1H), 6.35 (dd, 1H), 6.40 (dd, 1H), 6.54 (t, 1H), 6.80 (t, 1H), 6.9-7.0 (m, 7H), 7.26 (d, 1H), 7.33 (d,1H), 7.40 (s, 1H), 8.17 (d, 1H).

Additional examples of 3-[(3-phenoxyphenyl)[[3-(heteroaryl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 33.

Example Table 33. 3-[(3-phenoxyphenyl)[[3-(heteroaryl)phenyl]methyl]amino]- 1,1,1-trifluoro-2-propanols

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 589 3-methyl-pyridin-2-yl 479.1949 479.1946 590 pyridin-3-yl 465.1790 465.1778 591 pyridin-4-yl 465.1790 465.1821

EXAMPLE 592

3-[(3-phenoxyphenyl)[[3-(2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-592A) To a dioxane (20 mL) solution of 3-bromobenzaldehyde (0.63 mL, 5.4 mmol) was added 2-(tributylstannyl)furan (1.89 mL, 6.00 mL) and Pd(PPh₃)₂Cl₂ (0.21 g, 0.30 mmol). The mixture was heated to reflux under argon for 1.5 h. The cooled mixture was poured into a mixture of saturated KF and ethyl acetate and stirred 18 h. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.80 g (86%) of the desired 3-(2-furanyl)benzaldehyde product as an yellow oil which solidified upon standing. MS: m/z=173.1 [M+H]⁺.

EX-592B) To a 1,2-dichloroethane (7 mL) solution of aldehyde (0.40 g, 2.3 mmol) from EX-592A was added 3-phenoxyaniline (0.43 g, 2.3 mmol), NaB(OAc)₃H (0.64 g, 3.0 mmol) and acetic acid (0.15 mL, 2.6 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 0.74 g (94%) of the desired N-(3-phenoxyphenyl)[[3-(2-furanyl)phenyl]methyl]amine product as an yellow oil which was used without further purification. MS: m/z=342.3 [M+H]⁺.

To a dichloromethane (3 mL) solution of amine (0.74 g, 2.2 mmol) from EX-592B was added 1,1,1-trifluoro-2,3-epoxypropane (0.28 mL, 3.3 mmol) and Yb(OTf)₃ (0.136 g, 0.20 mmol). The cloudy solution was stirred at room temperature for 4 days, then diluted with diethyl ether, and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.49 g (49%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-furanyl )phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil, >98% pure by HPLC analysis. Anal. calcd. for C₂₆H₂₂NO₃F₃.0.5 EtOH.0.3 H₂O: C, 67.30; H, 5.35; N, 2.91. Found: C, 67.12; H, 5.12; N, 2.89. HRMS calcd. 454.1630 [M+H]⁺, found: 454.1635. ¹H NMR (C₆D₆) δ2.15 (d, 1H), 3.21 (dd, 1H), 3.50 (dd, 1H), 3.81 (m, 1H), 4.24 (s, 2H), 6.09 (dd, 1H), 6.33 (d, 1H), 6.35 (d, 1H), 6.44 (dd, 1H), 6.52 (t, 1H), 6.79 (m, 1H), 6.81 (s, 1H), 6.9-7.0 (m, 7H), 7.44 (d, 1H), 7.47 (s, 1H).

Additional examples of 3-[(3-phenoxyphenyl)[[4-substituted-3-(2-furanyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 34.

Example Table 34. 3-[(3-phenoxyphenyl)[[4-substituted-3-(2-furanyl)- phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 593 F 472.1536 472.1530 594 Me 468.1787 468.1783

EXAMPLE 595

3-[(3-phenoxyphenyl)[[3-(2-thienyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-595A) To a 1,2-dichloroethane (90 mL) solution of 3-bromobenzaldehyde (5.60 g, 30.3 mmol) was added 3-phenoxyaniline (5.60 g, 30.2 mmol), NaB(OAc)₃H (8.26 g, 39.0 mmol) and acetic acid (1.8 mL, 31.0 mmol). The cloudy solution was stirred at room temperature for 1.5 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 10.49 g (98%) of the desired N-(3-phenoxyphenyl)[(3-bromophenyl)methyl]amine product as a light brown oil. ¹H NMR (CDCl₃) δ4.26 (s, 2H), 6.27 (s, 1H), 6.38 (d, 2H), 7.00 (d, 2H), 7.13 (m, 2H), 7.19 (t, 1H), 7.26 (d, 1H), 7.30 (m, 2H), 7.38 (d, 1H), 7.96 (s, 1H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) and the formation of the benzyl peak (δ4.26) in the ¹H NMR spectrum.

EX-595B) To a dichloromethane (15 mL) solution of amine from EX-595A (6.01 g, 17.0 mmol) was added 1,1,1-trifluoro-2,3-epoxypropane (1.75 mL, 20.3 mmol) and Yb(OTf)₃ (1.05 g, 1.69 mmol). The cloudy solution was stirred at room temperature for 24 h, diluted with diethyl ether, and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 3-8% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 4.71 g (60%) of the desired 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C₂₂H₁₉NO₂F₃Br.0.41 EtOH: C, 56.49; H, 4.46; N, 2.89. Found: C, 56.15; H, 4.22; N, 2.92. HRMS calcd. 466.0629 [M+H]⁺, found: 466.0598.

To a dioxane (5 mL) solution of aminopropanol from EX-595B (0.38 g, 0.82 mmol) was added 2-(tributylstannyl)thiophene (0.29 mL, 0.90 mmol) and Pd(PPh₃)₂Cl₂ (0.040 g, 0.057 mmol). The mixture was heated to reflux under argon for 18 h. The cooled mixture was poured into a mixture of 10% aq. KF and ethyl acetate and stirred 1 h. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5-15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.17 g (45%) of the desired 3-[(3-phenoxy-phenyl)[[3-(2-thienyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C₂₆H₂₂NO₂F₃S.0.62 EtOH: C, 65.69; H, 5.20; N, 2.81. Found: C, 65.36; H, 4.84: N, 2.81. HRMS calcd. 470.1402 [M+H]⁺, found: 470.1392. ¹H NMR(CDCl₃) δ2.60(brs, 1H), 3.64(dd, 1H), 3.89 (dd, 1H), 4.37 (m, 1H), 4.68 (s, 2H), 6.42 (dd, 1H), 6.45 (t, 1H), 6.55 (dd, 1H), 6.98 (dd. 2H), 7.1 (m, 3H), 7.20 (t, 1H), 7.2-7.3 (m, 5H), 7.43 (s, 1H), 7.52 (d, 1H).

EXAMPLE 596

3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

To a THF (4 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh₃)₄. The resulting yellow solution was refluxed under N₂ for 18 h. The cooled solution was poured into saturated aq. NH₄Cl, extracted with ethyl acetate, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.39 g (62%) of the desired 3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C₂₉H₂₆NO₂F₃.0.4 EtOH: C, 72.17; H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd. 478.1994 ([M+H]⁺, found: 478.1984. ¹H NMR (C₆D₆) δ1.58 (d, 1H), 3.22 (dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34 (dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).

Additional examples of 3-[(3-phenoxyphenyl)[[3-(alkyl-or cycloalkyl-)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 35.

Example Table 35. 3-[(3-phenoxyphenyl)[[3-(alkyl- or cycloalkyl-)phenyl] methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 597 3-methylbutyl 458.2307 458.2295 598 2-methylpropyl 444.2150 444.2157 599 cyclopropyl 428.1837 428.1806

EXAMPLE 600

3-[(3-phenoxyphenyl)[[2′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]methyl]amino]-1,1,1-trifluoro-2-propanol

To a toluene (8 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol (0.51 g, 1.1 mmol) from EX-595B was added 2-(tri-fluoromethyl)phenylboronic acid (0.33 g, 1.7 mmol) and DMF (3 mL). To the resulting solution was added K₂CO₃ (0.31 g, 2.2 mmol) and Pd(PPh₃)₄ (0.060 g, 0.05 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.32 g (55%) of the desired 3-[(3-phenoxyphenyl)[[(2′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]methyl]amino]-1,1,1-tri-fluoro-2-propanol product as a colorless oil. Anal. calcd. for C₂₉H₂₃NO₂F₆.0.8 EtOH: C, 64.67; H, 4.93; N, 2.46. Found: C, 64.53; H, 4.69; N, 2.49. HRMS calcd. 532.1711 [M+H]⁺, found: 532.1708. ¹H NMR (C₆D₆) δ1.72 (d, 1H), 3.17 (dd, 1H), 3.46 (dd, 1H), 3.72 (m, 1H), 4.23 (s, 2H), 6.33 (dd, 1H), 6.43 (dd, 1H), 6.52 (t, 1H), 6.82 (m, 2H), 6.9-7.1 (m, 11H). 7.43 (d, 1H).

EXAMPLE 601

3-[(3-phenoxyphenyl)[[3-(3-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-601A) To a toluene (10 mL) solution of 3-bromofuran (0.54 mL, 6.0 mmol) was added 3-formylphenylboronic acid (1.00 g, 6.7 mmol) and DMF (4 mL). To the resulting solution was added K₂CO₃ (1.85 g, 13.4 mmol) and Pd(PPh₃)₄ (0.40 g, 0.35 mmol). The slurry was heated to reflux under argon for 2 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.10 g (10%) of the desired 3-(3-furanyl)benzaldehyde product as a yellow oil. MS: m/z=173.0 [M+H]⁺.

EX-601B) To a 1,2-dichloroethane (3 mL) solution of the aldehyde (0.10 g, 0.58 mmol) from EX-601A was added 3-phenoxyaniline (0.11 g, 0.59 mmol), NaB(OAc)₃H (0.16 g, 0.75 mmol) and acetic acid (0.040 mL, 0.70 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 0.20 g (100%) of the desired N-3-phenoxyphenyl)-[[3-(3-furanyl)phenyl]methyl]amine product as a yellow oil which was used without further purification. ¹H NMR (CDCl₃) δ4.1 (br s, 1H), 4.30 (s, 2H), 6.29 (d, 1H), 6.32 (dd, 1H), 6.39 (dd, 1H), 6.66 (s, 1H), 6.95-7.05 (m, 4H), 7.2-7.5 (m, 7H), 7.70 (s, 1H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) and the formation of the benzyl peak (δ4.30) in the ¹H NMR spectrum.

To a CH₃CN (2 mL) solution of amine (0.20 g, 0.58 mmol) from EX-601B was added 1,1,1-trifluoro-2,3-epoxypropane (0.10 mL, 1.2 mmol) and Yb(OTf)₃ (0.035 g, 0.056 mmol). The cloudy solution was stirred in a sealed flask at 40° C. After 18 h, additional 1,1,1,-trifluoro-2,3-epoxypropane (0.20 mL, 2.4 mmol) and Yb(OTf)₃ (0.035 g, 0.056 mmol) were added, and the mixture was heated an additional 4 h, diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.14 g (53%) of the desired 3-[(3-phenoxyphenyl)[[3-(3-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil, >99% pure by HPLC analysis. Anal. calcd. for C₂₆H₂₂NO₃F₃.0.3 EtOH: C, 68.37; H, 5.13; N, 3.00. Found: C, 68.29; H, 5.09; N, 2.99. HRMS calcd. 454.1630 [M+H]⁺, found: 454.1635. ¹H NMR (C₆D₆) δ1.62 (d, 1H), 3.18 (dd, 1H), 3.48 (dd, 1H), 3.74 (m, 1H), 4.22 (s, 2H), 6.32 (dd, 1H), 6.35 (m, 1H), 6.44 (dd, 1H), 6.52 (t, 1H), 6.78 (m, 1H), 6.82 (d, 1H), 6.9-7.1 (m, 9H), 7.37 (s, 1H).

EXAMPLE 602

3-[(3-phenoxyphenyl)[[3-(1-methyl-1H-pyrrol-2-yl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-602A) To solution of N-methylpyrrole (0.97 mL, 11 mmol) in Et₂O (20 mL) was added neat TMEDA (1.5 mL, 10 mmol) and 1.6 M n-BuLi in hexanes (6.3 mL, 10 mmol). The solution was heated to reflux under N₂ for 1 h and then cooled to −78° C. A 1.0 M solution of Me₃SnCl in THF was added over 15 min, and the resulting solution stirred for 30 min at −78° C. After warming to room temperature, 3-bromo-benzaldehyde (0.70 mL, 6.0 mmol), Pd(PPh₃)₂Cl₂ (0.25 g, 0.35 mmol) and dioxane (10 mL) were added. The slurry was heated to reflux for 18 h. The cooled mixture was poured into a mixture of saturated KF and ethyl acetate and stirred 15 min. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.45 g (24%) of the desired 3-(1-methyl-1H-pyrrol-2-yl)benzaldehyde product as a yellow oil. MS: m/z=186.2 [M+H]⁺.

EX-602B) To a 1,2-dichloroethane (10 mL) solution of aldehyde (0.45 g, 2.4 mmol) from EX-602A was added 3-phenoxyaniline (0.45 g, 2.4 mmol), NaB(OAc)₃H (0.67 g, 3.2 mmol) and acetic acid (0.15 mL, 2.4 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 0.67 g (79%) of the desired N-(3-phenoxyphenyl)[[3-(1-methyl-1H-pyrrol-2-yl)phenyl]methyl]amine product as a yellow oil which was used without further purification. ¹H NMR (CDCl₃) δ3.60 (s, 3H), 4.15 (br s, 1H), 4.35 (s, 2H), 6.2-6.4 (m, 5H), 6.67 (s, 1H), 7.00-7.05 (m, 4H), 7.1-7.2 (m, 6H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) and the formation of the benzyl peak (δ4.35) in the ¹H NMR spectrum.

To a CH₃CN (2 mL) solution of amine (0.67 g, 1.9 mmol) from EX-602B was added 1,1,1-trifluoro-2,3-epoxypropane (0.33 mL, 3.8 mmol) and Yb(OTf)₃ (0.120 g, 0.19 mmol). The cloudy solution as stirred in a sealed flask at 40° C. for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.57 g (66%) of the desired 3-[(3-phenoxyphenyl)[[3-(1-methyl-1H-pyrrol-2-yl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil, >99% pure by HPLC analysis. Anal. calcd. for C₂₇H₂₅N₂O₂F₃.0.9 EtOH: C, 68.10; H, 6.03; N, 5.51. Found: C, 68.36; H, 5.94; N, 5.65. HRMS calcd. 467.1946 [M+H]⁺, found: 467.1950. ¹H NMR (C₆D₆) δ2.01 (d, 1H), 2.97 (s, 3H), 3.21 (dd, 1H), 3.49 (dd, 1H), 3.78 (m, 1H), 4.28 (s, 2H), 6.3-6.4 (m, 4H), 6.45 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m, 10H).

EXAMPLE 603

3-[(3-phenoxyphenyl)[[3-(2-pyrimidinyl)phenyl]methyl]amino]1,1,1-trifluoro-2-propanol

EX-603A)To a toluene (15 mL) solution of 2-chloropyrimidine (1.00 g, 8.7 mmol) was added 3-formylphenylboronic acid (1.42 g, 9.5 mmol) and DMF (8 mL). To the resulting solution was added K₂CO₃ (2.63 g, 19.0 mmol) and Pd(PPh₃)₄ (0.52 g, 0.45 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.63 g (39%) of the desired 3-(2-pyrimidinyl)benzaldehyde product as a brown oil which solidified upon standing. MS: m/z=185.1 [M+H]⁺.

EX-603B) To a 1,2-dichloroethane (10 mL) solution of aldehyde (0.62 g, 3.4 mmol) from EX-603A was added 3-phenoxyaniline (0.62 g, 3.4 mmol), NaB(OAc)₃H (0.93 g, 4.4 mmol) and acetic acid (0.20 mL, 3.4 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 1.19 g (99%) of the desired N-(3-phenoxyphenyl)-[[3-(2-pyrimidinyl)phenyl]methyl]amine product as a brown oil which was used without further purification. MS: m/z=354.2 [M+H]⁺.

To a CH₃CN (4 mL) solution of amine (1.19 g, 3.4 mmol) from EX-603B was added 1,1,1,-trifluoro-2,3-epoxypropane (0.585 mL, 6.8 mmol) and Yb(OTf)₃ (0.112 g, 0.18 mmol). The cloudy solution was stirred in a sealed flask at 40° C. After 18 h, more 1,1,1-trifluoro-2,3-epoxypropane (0.585 mL, 6.8 mmol) and Yb(OTf)₃ (0.112 g, 0.18 mmol) were added, and the slurry was heated an additional 4 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by silica gel flash chromatography eluting with 25% ethyl acetate in hexane gave an oil which was dissolved in EtOH, concentrated and dried in vacuo to give 0.33 g (21%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-pyrimidinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a pale yellow oil, >99% pure by HPLC analysis. Anal. calcd. for C₂₆H₂₂N₃O₂F₃.0.5 EtOH: C, 66.39; H, 5.16; N, 8.60. Found: C, 66.26; H, 4.85; N, 8.60. HRMS calcd. 466.1742 [M+H]⁺, found: 466.1724. ¹H NMR (C₆D₆) δ2.28 (br s, 1H), 3.27 (dd, 1H), 3.50 (dd, 1H), 3.78 (m, 1H), 4.26 (m, 2H), 6.08 (t, 1H), 6.39 (dd, 1H), 6.52 (t, 1H), 6.75 (m, 1H), 6.9-7.0 (m, 6H), 7.18 (t, 1H), 8.12 (d, 2H), 8.58 (s, 1H), 8.66 (d, 1H).

EXAMPLE 604

3-[(3-phenoxyphenyl)[[3-(2-furanyl)-4-(4-morpholinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-604A) To a pyridine (15 mL) solution of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol) was added morpholine (0.5 mL, 5.7 mmol) and K₂CO₃ (0.69 g, 5.0 mmol), and the slurry was refluxed for 18 h. The solvent was removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO₄) and evaporated to a yellow oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave 0.77 g (58%) of the desired 3-bromo-4-(4-morpholinyl)benzaldehyde product as an white solid. ¹H NMR (CDCl₃) δ3.18 (m, 4H), 3.90 (m, 4H), 7.10 (d, 1H), 7.78 (d, 1H), 8.07 (s, 1H), 9.83 (s, 1H).

EX-604B) To a dioxane (8 mL) solution of the aldehyde from EX-604A (0.77 g, 2.8 mmol) was added 2-(tributylstannyl)furan (1.07 mL, 3.42 mmol) and Pd(PPh₃)₂Cl₂ (0.12 g, 0.17 mmol). The mixture was heated to reflux under argon for 18 h. The cooled mixture was poured into a mixture of saturated aq. KF and ethyl acetate and stirred 3 h. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO₄) and evaporated to a yellow oil. Purification by silica gel flash chromatography eluting with 20% ethyl acetate in hexane gave 0.61 g (84%) of the desired 3-(2-furanyl)-4-(4-morpholinyl)benzaldehyde product as a yellow oil. MS: m/z=258.1 [M+H]⁺.

To a 1,2-dichloroethane (6 mL) solution of aldehyde (0.59 g, 2.0 mmol) from EX-604B was added N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.50 g, 1.9 mmol), NaB(OAc)₃H (0.52 g, 2.5 mmol) and acetic acid (0.12 mL, 2.1 mmol). The cloudy solution was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to give an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave 0.25 g (25%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-furanyl)-4-(4-morpholinyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a white foam, >99% pure by HPLC analysis. Anal. calcd. for C₃₀H₂₉N₂O₄F₃: C, 66.91; H, 5.43; N, 5.20. Found: C, 66.54; H, 5.67; N, 5.02. HRMS: calcd. 539.2187 [M+H]⁺, found: 539.2158. ¹H NMR (C₆D₆) δ1.73 (d, 1H), 2.55 (m, 4H), 3.23 (dd, 1H), 3.50 (dd, 1H), 3.52 (m, 4H), 3.75 (m, 1H), 4.25 (s, 2H), 6.21 (dd, 1H), 6.36 (dd, 1H), 6.34 (dd, 1H), 6.56 (t, 1H), 6.69 (d, 1H), 6.8 (m, 2H), 6.9-7.0 (m, 5H), 7.09 (t, 1H), 7.22 (d, 1H), 7.34 (d, 1H).

EXAMPLE 605

3-[(3-phenoxyphenyl)[[3-(2-pyrimidinyloxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-605A) A slurry of 3-hydroxybenzaldehyde (1.22 g, 10 mmol), 2-chloropyrimidine (1.14 g, 10 mmol) and K₂CO₃ (1.65 g, 12 mmol) in DMSO (20 mL) was heated to 100° C. for 1 h. The cooled mixture was poured into water and extracted with Et₂O. The organic layer was washed with 2.5 N NaOH, 1 N HCl, saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 1.42 g (71%) of the desired 3-(2-pyrimidinyl-oxy)benzaldehyde product as a white solid which was used without further purification. ¹H NMR (C₆D₆) δ7.12 (t, 1H), 7.54 (m, 1H), 7.66 (t, 1H), 7.78 (m, 1H), 7.83 (m, 1H), 8.64 (d, 2H), 10.05 (s, 1H).

To a 1,2-dichloroethane (10 mL) solution of aldehyde (0.56 g, 2.8 mmol) from EX-605A was added N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.83 g, 2.8 mmol), NaB(OAc)₃H (0.77 g, 3.6 mmol) and acetic acid (0.84 mL, 15 mmol). The cloudy solution was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to give an oil. Purification by flash chromatography on silica gel eluting with 2% methanol in CH₂Cl₂ gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.28 g (21%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-pyrimidinyloxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil, >99% pure by HPLC analysis. Anal. calcd. for C₂₆H₂₂N₃O₃F₃.0.4 EtOH: C, 64.39; H, 4.92; N, 8.41. Found: C, 64.22; H, 4.87; N, 8.53. HRMS calcd. 482.1692 [M+H]⁺, found: 482.1698. ¹H NMR (C₆D₆) δ3.12 (d, 1H), 3.16 (dd, 1H), 3.49 (d, 1H), 3.79 (m, 1H), 4.12 (dd, 1H), 5.88 (t, 1H), 6.31 (dd, 1H), 6.41 (dd, 1H), 6.51 (t, 1H), 6.65 (t, 1H), 6.80 (t, 1H), 6.85-7.05 (m, 8H), 7.82 (d, 2H).

EXAMPLE 606

3-[(3-phenoxyphenyl)[([1,1′-biphenyl]-3-ylmethyl)amino]-1,1,1-trifluoro-2-propanol

EX-606A) To an ethylene glycol dimethyl ether (10 mL) solution of 3-bromo-benzaldehyde (0.63 mL, 5.4 mmol) was added phenylboronic acid (0.73 g, 6.0 mmol), 2 M Na₂CO₃ (10 mL) and Pd(PPh₃)₄ (0.35 g, 0.30 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave 0.77 g (98%) of the desired [(1,1′-biphenyl)-3-yl]-carboxaldehyde product as a colorless oil which solidified upon standing. ¹H NMR (C₆D₆) δ7.45 (m, 3H), 7.65 (m, 3H), 7.70 (dd, 2H), 8.15 (m, 1H), 10.13 (s, 1H).

EX-606B) To a 1,2-dichloroethane (12 mL) solution of aldehyde (0.77 g, 4.2 mmol) from EX-606A was added 3-phenoxyaniline (0.78 g, 4.2 mmol), NaB(OAc)₃H (1.16 g, 5.5 mmol) and acetic acid (0.25 mL, 4.2 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield ^(1.49) g (100%) of the desired N-(3-phenoxyphenyl)([1,1′-biphenyl]-3-ylmethyl)amine product as a colorless oil which was used without further purification. 1H NMR (CDCl₃) δ4.35 (s, 2H), 6.35 (m, 2H), 6.44 (d, 1H), 6.97 (d, 2H), 7.05 (t, 1H), 7.12 (t, 1H), 7.3 -7.4 (m, 7H), 7.49 (d, 1H), 7.56 (m, 3H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) and the formation of the benzyl peak (δ4.35) in the ¹H NMR spectrum.

To a CH₃CN (4 mL) solution of amine (1.48 g, 4.2 mmol) from EX-606B was added 1,1,1-trifluoro-2,3-epoxypropane (0.475 mL, 5.5 mmol) and Yb(OTf)₃ (0.26 g, 0.42 mmol). The cloudy solution was stirred in a sealed flask at 40° C. for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.65 g (34%) of the desired 3-[(3-phenoxyphenyl)]([1,1′-biphenyl]-3-ylmethyl)amino]-1,1,1-trifluoro-2-propanol product as a colorless oil which solidified upon standing, >99% pure by HPLC analysis. Anal. calcd. for C₂₈H₂₄NO ₂F₃.0.05 CH₂Cl₂: C, 72.03; H, 5.19; N, 2.99. Found: C, 71.67; H, 5.10; N, 2.94. HRMS calcd. 464.1837 [M+H]⁺, found: 464.1834. ¹H NMR (C₆D₆) δ1.43 (d, 1H), 3.17 (dd, 1H), 3.46 (dd, 1H) 3.70 (m, 1H), 4.26 (s, 2H), 6.32 (dd, 1H), 6.44 (dd, 1H), 6.52 (t, 1H), 6.77 (m, 1H), 6.85-6.95 (m, 5H), 7.1 (m, 3H), 7.16 (t, 2H), 7.26 (s, 1H), 7.27 (d, 1H), 7.40 (dd, 2H).

EXAMPLE 607

3-[(3-phenoxyphenyl)[[3-cyclopentylphenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-607A) To a 1,2-dichloroethane (12 mL) solution of 3-cyclopentylbenzaldehyde (0.69 g, 4.0 mmol: P. L. Omstein et al., J. Med. Chem. 1998, 41, 358-378) was added 3-phenoxyaniline (0.73 g, 4.0 mmol), NaB(OAc)₃H (1.08 g, 5.1 mmol) and acetic acid (0.24 mL, 4.2 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave 0.30 g (22%) of the desired N-(3-phenoxyphenyl)-[[3-cyclopentylphenyl]methyl]amine product as a colorless oil. ¹H NMR (CDCl₃) δ1.55 (m, 2H), 1.63 (m, 2H), 1.78 (m, 2H), 2.02 (m, 2H), 2.94 (m, 1H), 4.10 (m, 1H), 4.22 (m, 2H), 6.35 (m, 3H), 7.0-7.2 (m, 10H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) and the formation of the benzyl peak (δ4.22) in the ¹H NMR spectrum.

To a CH₃CN (0.9 mL) solution of amine (0.30 g, 0.87 mmol) from EX-607A was added 1,1,1-trifluoro-2,3-epoxypropane (0.15 mL, 1.7 mmol) and Yb(OTf)₃ (0.080 g, 0.13 mmol). The cloudy solution was stirred in a sealed flask at 50° C. for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.19 g (48%) of the desired 3-[(3-phenoxyphenyl)[[3-cyclopentyl]phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil which solidified upon standing, >99% pure by HPLC analysis. Anal. calcd. for C₂₇H₂₈NO₂F₃.0.4 EtOH: C, 70.45; H, 6.47; N, 2.96. Found: C, 70.21; H, 6.39; N, 2.94. HRMS calcd. 456.2150 [M+H]⁺ found: 456.2143. ¹H NMR (C₆D₆) δ1.43 (m, 4H), 1.58 (m, 2H), 1.62 (d, 2H), 1.85 (m, 2H), 2.71 (m, 1H), 3.22 (dd, 1H), 3.49 (dd, 1H), 3.73 (m, 1H), 4.26 (s, 2H), 6.35 (dd, 1H), 6.43 (dd, 1H), 6.55 (t, 1H), 6.8 (m, 2H), 6.95-7.05 (m, 8H).

EXAMPLE 608

3-[(3-phenoxyphenyl)[[3-(tetrahydro-2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-608A) Trifluoromethanesulfonic anhydride (2.0 mL, 11.9 mmol) was added dropwise over 5 minutes to a slurry of 3-hydroxybenzaldehyde (1.11 g, 9.09 mmol) in dichloromethane (40 mL) at −78° C. To this slurry was added neat N,N-di-isopropyl-ethylamine (2.4 mL, 13.8 mmol) dropwise over 5 min, and the resulting yellow solution was allowed to warm to room temperature. After 30 min at room temperature, the dark solution was diluted with dichloromethane and washed with 2.5 N NaOH, 1 N HCl, saturated NaHCO₃ and brine. The organic layer was dried (MgSO₄) and evaporated to give a red oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave 1.70 g (74%) of the desired triflate ester product as a pale yellow oil. MS: m/z=254 [M+H]⁺.

EX-608B) To a mixture of Pd₂(dba)₃ (120 mg, 0.13 mmol) and P(o-tolyl)₃ (150 mg, 0.50 mmol) in toluene (15 mL) was added the triflate ester from EX-608A (1.70 g, 6.7 mmol), N,N-di-isopropylethylamine (3.50 mL, 20.1 mmol) and 2,3-dihydrofuran (2.53 mL, 33.5 mmol). The solution was heated to 70° C. in a sealed flask under argon for 18 h. The cooled solution was then diluted with ethyl acetate and washed with water, 1 N HCl, saturated NaHCO₃ and brine.

The organic layer was dried (MgSO₄) and evaporated to give a red oil. The major product was isolated by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane and gave 0.72 g (62%) of the desired 3-(dihydro-2-furanyl)benzaldehyde product as a cloudy yellow oil. MS: m/z=175.1 [M+H]⁺.

EX-608C) A THF (15 mL) solution of the aldehyde from EX-608B (0.70 g, 4.0 mmol) and 2,6-lutidine (0.46 mL, 4.0 mmol) was stirred in a hydrogen atmosphere (50 psi) in the presence of 10% Pd/C (0.29 g) for 18 h at room temperature. The slurry was filtered through celite, and the solvent was removed. The residue was taken up in ethyl acetate and washed with 1 N HCl and brine. The organic layer was dried (MgSO₄) and evaporated to give 0.50 g (70%) of the desired 3-(tetrahydro-2-furanyl)phenylmethanol product as a yellow oil. The formation of the desired product was monitored by the disappearance of the aldehyde (δ˜10) and olefin peaks in the ¹H NMR spectrum.

EX-608D) A slurry of the phenylmethanol product from EX-608C (0.50 g, 2.8 mmol) and MnO₂ (2.10 g, 24.3 mmol) in dichloromethane (15 mL) was refluxed for 3 h. The slurry was filtered through celite, and the filtrate was evaporated to a yellow oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave 0.19 g (45%) of the desired aldehyde product as a pale yellow oil. GCMS: m/z=177 [M+H]⁺.

EX-608E) To a 1,2-dichloroethane (4 mL) solution of the aldehyde (0.19 g, 1.1 mmol) from EX-608D was added 3-phenoxyaniline (0.20 g, 1.1 mmol), NaB(OAc)₃H (0.30 g, 1.4 mmol) and acetic acid (0.065 mL, 1.1 mmol). The cloudy solution was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to yield 0.32 g (84%) of the desired N-(3-phenoxyphenyl)-[[3-(tetrahydro-2-furanyl)phenyl]methyl]amine product as a yellow oil which was used without further purification. The formation of the desired product was monitored by TLC.

To a CH₃CN (1 mL) solution of the amine (0.32 g, 0.93 mmol) from EX-608E was added 1,1,1-trifluoro-2,3-epoxypropane (0.24 mL, 2.8 mmol) and Yb(OTf)₃ (0.115 g, 0.18 mmol). The cloudy solution was stirred in a sealed flask at 40° C. for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.13 g (30%) of the desired 3-[(3-phenoxyphenyl)[[3-(tetrahydro-2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C₂₆H₂₆NO₃F₃.0.5 EtOH: C, 67.33; H, 6.04; N, 2.94. Found: C, 67.49; H, 6.08; N, 2.91. HRMS calcd.458.1943 [M+H]⁺, found: 458.1937. ¹H NMR (C₆D₆) δ0.45 (d, 1H), 1.43 (m, 3H), 1.79 (m, 1H), 1.99 (m, 1H), 3.24 (m, 1H), 3.43 (m, 1H), 3.76 (m, 2H), 4.24 (s, 2H), 4.60 (t, 1H), 6.35 (m, 1H), 6.43 (dd, 1H), 6.54 (dd, 1H), 6.8 (m, 2H), 6.9-7.0 (m, 7H), 7.15 (d, 1H).

EXAMPLE 609

4-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]phenol

A 1,2-dichloroethane (4 mL) solution of N-[(4-methoxyphenoxy)phenyl]-3-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.33 g, 0.62 mmol) and boron tribromide-methyl sulfide complex (2.5 mL, 1.0 M in CH₂Cl₂, 2.5 mmol) was refluxed for 8 h under argon. The reaction was diluted with Et₂O and washed with water, 1 N NaOH and saturated aq. NH₄Cl.

The organic layer was dried (MgSO₄) and evaporated to give a red oil. Purification by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.082 g (25%) of the desired 4-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]phenol product as a light red oil. Anal. calcd. for C₂₄H₂₀NO₄F₇.0.35 EtOH.0.65 H₂O: C, 54.21; H, 4.31; N, 2.56. Found: C, 54.20; H, 4.30; N, 2.55. HRMS calcd. 520.1359 [M+H]⁺, found: 520.1325. ¹H NMR (C₆D₆) δ1.96 (d, 1H), 3.09 (dd, 1H), 3.43 (dd, 1H), 3.74 (m, 1H), 4.10 (s, 2H), 4.52 (s, 1H), 5.09 (tt, 1H), 6.17 (dd, 1H), 6.4 (m, 4H), 6.66 (d, 1H), 6.8-6.9 (m, 6H).

EXAMPLE 610

3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-(trifluoromethyl)oxazolidine

A toluene solution (5 mL) of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.45 g, 2.0 mol) and N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.60 g, 2.0 mmol) was refluxed in the presence of molecular sieves and Znl₂ (˜5 mg) for 18 h under N₂. The reaction mixture was filtered to remove the sieves, and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO₄) and evaporated to give 0.92 g (92%) of the desired 3-(3-phenoxyphenyl)-2-2-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-5-(trifluoromethyl)oxazolidine product as a colorless oil. The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) in the ¹H NMR spectrum. HRMS calcd. 502.1253 [M+H]⁺, found: 502.1220.

EXAMPLE 611

4-[bis-[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-butanol

EX-611A) The 2-hydroxy-1,1,1-trifluorobutyronitrile (5.0 g, 36 mmol; H. C. Brown et ad. J. Org. Chem. 60, 41-46, 1995) was added slowly to a stirred suspension of LiAlH₄ (1.7 g, 43.7 mmol) in 8 mL of dry diethyl ether at 0-5° C. The mixture was stirred at this temperature for 30 min, heated for 45 min, then stirred at room temperature for 2 h. The reaction mixture was quenched with 5.5 mL of aq. sat. Na₂SO₄ and stirred for 1 h. The mixture was filtered through a celite pad, and the pad was washed with ether. The filtrate and ether washings were collected and evaporated to give 4.2 g (82%) of crude 4amino-2-hydroxy-1,1,1-trifluorobutane product as a brownish solid. HRMS calcd. for C₄H₈NOF₃: 144.0636 [M+H]⁺, found 144.0622.

The 4-amino-2-hydroxy-1,1,1,-trifluorobutane (0.57 g, 4 mmol) from EX-611 A and 3-(trifluoromethoxy)benzyl bromide (2.04 g, 8.0 mmol) were dissolved in 10 mL of anhydrous ethanol. Potassium carbonate (1.10 g, 8 mmol) was added, and the mixture was heated to reflux for 3 days, at which time HPLC analysis indicated the formation of product, as confirmed by MS. The reaction mixture was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄, and evaporated to give crude product, which was purified by flash column chromatography on silica gel eluting with 1:10:0.01 to 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 0.53 (27%) of the desired 4-[bis-[[3-(tri-fluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-butanol product as a yellow oil. ¹H NMR (CDCl₃) δ7.37 (t, 2H), 7.23 (d, 2H), 7.14 (d, 4H), 5.68 (bs, 1H), 3.98 (m, 1H), 3.76 (d, 2H). 3.45 (d, 2H), 2.78 (dd, 2H), 1.90 (m, 1H), 1.83 (m, 1H). ¹⁹F NMR (CDCl₃) δ−58.27 (s, 6F), −80.54 (d, 3F). HRMS calcd. for C₂₀H₁₈NO₃ F₉: 492.1221 [M+H]⁺, found: 492.1184.

EXAMPLE 612

N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamide

EX-612A) Methyl 3-(bromomethyl)benzoate (7.2 g, 0.031 mol) was added dropwise to a solution of 3-phenoxyaniline (20.5 g, 0.11 mol) in 160 mL of cyclohexane. The reaction mixture was refluxed overnight then cooled to room temperature and diluted with water and methylene chloride. The layers were separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo to give a dark oil. The crude product was purified by reverse phase HPLC eluting with 20% to 90% acetonitrile in water to afford 6.2 g (59%) of the desired methyl 3-[[(3-phenoxyphenyl)amino]methyl]benzoate product as a yellow oil. ESMS m/z=334 [M+H]⁺.

EX-612B) To a mixture of methyl 3-[[(3-phenoxyphenyl)amino]methyl]benzoate (6.2 g, 0.019 mol) from EX-612A and 1,1,1-trifluoro-2,3-epoxypropane (8.58 g, 0.077 mol) in 12 mL of acetonitrile was added ytterbium (III) trifluoromethanesulfonate (1.2 g, 0.0019 mol). The resulting mixture was heated at 50° C. in a sealed glass tube for 18 h. The reaction mixture was cooled to room temperature, then diluted with water and methylene chloride. The aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to afford 8.0 g (96%) of the desired methyl 3-[[(3-phenoxy-phenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate product as a yellow oil. Anal. calcd. for C₂₄H₂₂F₃NO₄.1.4 H₂O: C, 61.25; H, 5.31; N, 2.98. found: C, 61.52; H, 5.06; N, 2.89. HRMS calcd.: 446.1579 [M+H]⁺, found: 446.1596. ¹H NMR (CDCl₃) δ7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H). 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ−79.0 (d, 3F).

To a solution of N,N-dimethylamine hydrochloride (525 mg, 0.0064 mol) in 3.0 mL of toluene at −40° C. was added dropwise a 2.0 M solution of trimethylaluminum in toluene (3.2 mL, 0.0064 mol) over 15 min. The reaction mixture was warmed to room temperature and stirred for 2 h. To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (209 mg, 0.00047 mol) from EX-612B in 2.5 mL of toluene at −10 ° C. was slowly added the (N,N-dimethylamino)-chloromethylaluminum reagent (850 μL, 0.00085 mol). The reaction mixture was warmed to room temperature then heated at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and quenched with 10% aqueous potassium hydrogen phosphate. The organic layer was dried over MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate in hexane to afford 195 mg (91%) of the desired N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]-benzamide product as a pale yellow solid. Anal. calcd. for C₂₅H₂₅F₃N₂O₃.0.5 H₂O: C, 64.23; H, 5.61; N, 5.99. Found: C, 64.49; H, 5.77; N, 5.85. HRMS calcd. 459.1896 [M+H]⁺, found: 458.1887. ¹H NMR (C₆D₆) δ7.01-6.95 (m, 3H), 6.92-6.87 (m, 5H), 6.79 (t, 1H), 6.46 (s, 1H), 6.37 (t, 2H), 4.91 (bs, 1H), 4.26 (s, 2H), 4.10 (bq, 1H), 3.84 (dd, 1H), 3.38 (dd, 1H), 2.53 (bs, 31H), 2.14 (bs, 31H). ¹⁹F NMR (C₆D₆) δ−78.69 (d, 3F).

Additional examples of N,N-dialkyl- and N,N-cycloalkyl-3-[[(3-phenoxy-phenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamides can be prepared by one skilled in the art using similar methods, as shown in Example Table 36.

Example Table 36. N,N-dialkyl- and N,N-cycloalkyl-3-[[(3-phenoxyphenyl)- (3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamides.

Ex. Calculated Observed No. R_(SUB1) R_(SUB2) Mass [M + H]⁺ Mass [M + H]⁺ 613 methyl ethyl 473.2052 473.2055 614 methyl propyl 487.2209 487.2193 615 methyl butyl 501.2365 501.2357 616 —(CH₂CH₂CH₂CH₂)— 485.2052 485.2057

EXAMPLE 617

α,α-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol

To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxy-propyl)amino]methyl]benzoate (218 mg, 0.00049 mol) in 0.7 mL of tetrahydrofuran at 0° C. was slowly added a 3.0 M solution of methylmagnesium chloride in THF (650 μL, 0.0020 mol). The reaction mixture was warmed to room temperature, stirred for 2 h, then diluted with diethyl ether and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate:hexane to afford 174 mg (80%) of the desired α,α-dimethyl-3-[[(3-phenoxy-phenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol product as a slightly yellow oil. Anal. calcd. for C₂₅H₂₆F₃NO₃.0.5 H₂O: C, 66.07; H, 5.99; N, 3.08. found: C, 66.12; H, 6.34; N, 2.92. HRMS calcd. 466.1943 [M+H]⁺, found: 446.1938. ¹H NMR (CDCl₃) δ7.34 (s, 1H), 7.32-7.21 (m, 4H), 7.13 (t, 1H), 7.09-7.01 (m, 2H), 6.94 (d, 2H), 6.50 (d, 1H), 6.41 (s, 1H), 6.37 (d, 1H), 4.61 (s, 2H), 4.27 (bt, 1H), 3.81 (appd, 1H), 3.53 (dd, 1H), 3.33 (bs, 1H), 1.96 (bs, 1H), 1.51 (s, 6H). ¹⁹F NMR (CDCl₃) δ−78.88 (d, 3F).

EXAMPLE 618

3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol

To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxy-propyl)amino]methyl]benzoate (197 mg, 0.00044 mol) in 2.0 mL of dichloromethane at −40° C. was slowly added a 1.0 M solution of lithium aluminum hydride in THF (1.1 mL, 0.0011 mol). The reaction mixture was stirred at −40° C. for 1 h, then diluted with ethyl acetate and quenched with water. The organic layer was dried over MgSO₄ and concentrated in vacuo. The crude material was determined to contain a significant amount of unreacted starting material by HPLC at this stage. The crude material was resubjected to the reaction conditions using 2 mL of anhydrous tetrahydrofuran and 1.0 M lithium aluminum hydride (1.3 mL, 0.0013 mol) at −40° C. for 1 h, then diluted with ethyl acetate and quenched with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate:hexane to afford 99 mg (54%) of the desired 3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol product as a white solid. Anal. calcd. for C₂₃H₂₂F₃NO₃: C, 66.18; H, 5.31; N, 3.36. Found: C, 65.98; H, 5.39; N, 3.22. HRMS calcd. 418.1630 [M+H]⁺, found: 418.1636. ¹H NMR (C₆D₆) δ7.08-6.92 (m, 8H), 6.89-6.80 (m, 2H), 6.56 (s, 1H), 6.46 (d, 1H), 6.38 (d, 1H), 4.26 (s, 2H), 4.21 (d, 2H), 3.77 (appq, 1H), 3.52 (d, 1H), 1.92 (bs, 1H), 0.96 (bs, 1H). ¹⁹F NMR (C₆D₆) δ−78.91 (d, 3F).

EXAMPLE 619

α,α-bis(trifluoromethyl)-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol

To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)-amino]methyl]benzoate (331 mg. 0.00074 mol) and trimethyl(trifluoromethyl)silane (423 mg, 0.0030 mol) in 3.0 mL of toluene at room temperature was added a 1.0 M solution of tetrabutylammonium fluoride in THF (150 μL, 0.00015 mol) which had been dried over molecular sieves. The reaction mixture was heated at 40° C. for 18 h. HPLC analysis indicated incomplete reaction therefore additional trimethyl(trifluoro-methyl)silane (440 μL, 0.0030 mol) and tetrabutylammonium fluoride (150 μL, 0.00015 mol) were added, and the reaction mixture was heated to 50° C. in a sealed glass vial. After 2 h, HPLC analysis indicated no ester starting material remained. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate:hexane to afford 26 mg (6%) of the desired α,α-bis(trifluoromethyl)-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl) amino]methyl]benzenemethanol product as a yellow-brown oil. HRMS calcd. for C₂₅H₂₀F₉NO₃: 554.1378 [M+H]⁺, found: 554.1385. ¹H NMR (CDCl₃) δ7.69 (dd, 1H), 7.57 (apps, 1H), 7.52 (dd, 1H), 7.37 (t, 1H), 7.29-7.23 (m, 2H), 7.14 (t, 1H), 7.05 (t, 1H), 6.92 (d, 2H), 6.47 (d, 1H), 6.38 (d, 1H), 6.37 (s, 1H), 4.66 (s, 2H), 4.29 (m, 1H), 3.82 (d, 1H), 3.54 (dd, 1H). ¹⁹F NMR (CDCl₃) δ−75.81 (dq, 6F), −79.18 (d, 3F).

EXAMPLE 620

1-[3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]phenyl]-1-propanone

EX-620A) To a slurry of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (1.03 g, 0.0023 mol) and N,O-dimethyl-hydroxylamine hydrochloride (386 mg. 0.0040 mol) in 4.6 mL of tetrahydrofuran at −15° C. was added a 2.0 M solution of isopropylmagnesium chloride in THF (4.6 mL, 0.0092 mol) over 15 min. The reaction was stirred for 1 h at −15° C., then quenched with 20% aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:1 ethyl acetate:hexane to afford 0.72 g (66%) of the desired N-methoxy-N-methyl-3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamide product as an off-white solid. HRMS calcd. for C₂₅H₂₅N₂O₄F₃: 475.1845 [M+H]⁺, found: 475.1840.

To a solution of N-methoxy-N-methylbenzamide (208 mg, 0.00044 mol) from EX-620A in 2.2 mL of tetrahydrofuran at −15° C. was added a 1.0 M solution of ethyl-magnesium bromide in THF (950 μL, 0.0095 mol). The reaction mixture was slowly warmed to room temperature then left stirring overnight. HPLC analysis indicated unreacted starting material was still present so additional ethylmagnesium bromide (440 μL, 0.0044 mol) was added. After 3 h at room temperature, the reaction mixture was diluted with diethyl ether and quenched with 1N HCl. The aqueous layer was extracted with diethyl ether and the combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 121 mg (62%) of the desired 1-[3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)-amino]methyl]phenyl]-1-propanone product as a pale yellow oil. HRMS calcd. for C₂₅H₂₄F₃NO₃: 444.1787 [M+H]⁺, found: 444.1786. ¹H NMR (CDCl₃) δ7.83 (d, 1H), 7.78 (s, 1H), 7.38 (appq, 2H), 7.27 (appq, 2H), 7.15 (t, 1H), 7.06 (t, 1H), 6.94 (d, 2H), 6.48 (d, 1H), 6.39 (d, 1H), 6.37 (s, 1H), 4.68 (s, 2H), 4.35 (m, 1H), 3.88 (dd, 1H), 3.56 (dd, 1H), 2.95 (q, 2H), 1.20 (t, 3H). ¹⁹F NMR (CDCl₃) δ−79.17 (d, 3F).

Additional examples of 1-[3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]-phenyl]-1-alkanones can be prepared by one skilled in the art using similar methods, as shown in Example Table 37.

Example Table 37. 1-[3-[[(3-phenoxyphenyl) (3,3,3-trifluoro-2-hydroxy- propyl)amino]methyl]-phenyl]-1-alkanones.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 621 isobutyl 472.2130 472.2100

EXAMPLE 622

3-[[4-(phenylethynyl)-(3-(trifluoromethyl)phenyl][[3-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

The 3-[(3-(trifluoromethyl)4bromophenyl)[[3-(1,1,1-trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol (0.33 g, 0.648 mmol) and tributylstannylphenyl-acetylene (0.278 g, 0.712 mmol) were added to degassed 1,2-dichloroethane. The resulting mixture was stirred at room temperature for 10 min, then Pd(PPh₃)₂Cl₂ (0.032 g. 0.045 mmol) was added. The mixture was stirred 18 h at room temperature. More tributyl-stannylphenylacetylene (0.278 g, 0.712 mmol) and Pd(PPh₃)₂Cl₂ (0.032 g, 0.045 mmol) were added. The solution was refluxed for 72 h. The reaction mixture was diluted with diethyl ether and stirred in 10% aq. KF for 18 h. The organic layer was collected, dried over MgSO₄ and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 0.102 g (30%) of the desired 3-[[4-(phenylethynyl)-(3-(trifluoromethyl)phenyl]-[[3-(trifluoromethyl)phenyl]methyl]amino]1,1,1-trifluoro-2-propanol product as a pure yellow oil. Anal calcd. For C₂₆H₁₈NOF₉: C, 58.76; H, 3.41; N, 2.64. Found: C, 58.72; H, 3.67; N, 2.47. HRMS calcd. 532.1322 [M+H]⁺, found: 532.1304. ¹H NMR (CDCl₃) δ7.52 (m, 4H), 7.38 (dd, 2H), 7.32 (dd, 2H), 7.24 (dd, 1H), 7.00 (s, 1H), 6.78 (dd, 1H), 4.80 (s, 2H), 4.36 (m, 1H), 3.92 (d, 1H), 3.65 (m, 1H), 2.60 (d, 1H). ¹⁹F NMR (CDCl₃) δ−63.5 (s, 6F), −79.38 (d, 3F).

Additional examples of 3-[[4(heteroaryl)-(3-(trifluoromethyl)phenyl][[3-(tri-fluoromethyl)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 38.

Example Table 38. 3-[[4-heteroaryl)-(3-(trifluoromethyl)phenyl]-[[3- (trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB) Mass [M + H]⁺ Mass [M + H]⁺ 623 2-thienyl 514.0887 514.0912 624 2-furanyl 498.1037 498.1116

EXAMPLE 625

3-[4-bromo-3-(trifluoromethyl)phenyl[[3-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-625A) The α,α, α-trifluoro-m-tolualdehyde (3.63 g, 0.021 mol) was added neat to 4-bromo-3-trifluoromethylaniline (5.0 g, 0.021 mol). Dichloroethane (50 mL) was added followed by sodium triacetoxyborohydride (4.85 g, 0.023 mol) and acetic acid (1.42 g, 0.024 mol). The resulting mixture was stirred at room temperature for 18 h, then diluted with methylene chloride, quenched with sodium bicarbonate and extracted with methylene chloride. The organic layers were combined and dried over MgSO₄ and concentrated to give 6.97 g of the desired 3-[4bromo-3-(trifluoromethyl)-phenyl[[3-(trifluoromethyl)phenyl]methyl]amine product as a yellow oil, which was carried forward without purification. ESMS m/z=397 [M+H]⁺.

The amine product (6.97 g, 0.018 mol) from EX-625A was mixed with 1,1,1-trifluoro-2,3-epoxypropane (3.92 g, 0.035 mol) in a pressurized vial. A suspension of ytterbium triflate (1.08 g, 0.002 mol) in 2.0 mL of acetonitrile was added. The resulting mixture was stirred at room temperature for 18 h, then quenched with water and extracted with ethyl acetate. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 1.04 g (11%) of the desired 3-[4-bromo-3-(trifluoromethyl)phenyl[[3-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a pure yellow oil. Anal calcd. for C₁₈H ₃NOF₉Br: C, 42.38; H, 2.57; N. 2.75. Found: C, 42.16; H, 2.71; N, 2.71. HRMS calcd. 510.0115 [M+H]⁺, found: 510.0139. ¹H NMR (C₆D₆) δ7.40 (d, 2H), 7.20 (d, 1H), 7.10 (m, 2H), 6.98 (d, 1H), 6.18 (dd, 1H), 4.00 (s, 2H), 3.63 (m, 1H). 3.40 (d. 1H). 3.02 (m, 1H), 1.80 (d, 1H). ¹⁹ F NMR (C₆D₆) δ−62.35 (s, 3F), −65.00 (s, 3F), -78.58 (d,3F).

EXAMPLE 626

3-[[1-methyl-3-[3-(trifluoromethoxy)phenyl]propyl](3-phenoxyphenyl)amino]-1,1,1-trifluoro-2-propanol

EX-626A) Tetrabutylammonium iodide (0.4 g, 0.05 mol) was added to a well-stirred biphasic mixture of 12 mL of 50% NaOH and 20 mL of methylene chloride under a nitrogen atmosphere. A solution of 3-trifluoromethoxybenzaldehyde (4.0 g, 0.021 mol) and diethyl(2-oxopropyl)phosphonate (4.08 g, 0.021 mol) in 4.0 mL of methylene chloride was added dropwise to the stirred solution. The resulting mixture was stirred at room temperature for 15 min, then quenched with water and extracted with hexane. The hexane layer was dried over MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with 1:10 ethyl acetate in hexane to give 2.6 g (54%) of the desired 4-[3-(trifluoromethoxy)phenyl]-3-buten-2-one product as a yellow oil. ¹H NMR (CDCl₃) δ7.43 (m, 4H), 7.20 (d, 1H), 6.65 (d, 2H), 2.29 (s, 3H). ¹⁹F NMR (CDCl₃) δ−62.05 (s, 3F).

EX-626B) The product (1.0 g, 0.0004 mol) from EX-626A was dissolved in 25 mL of ethanol and the reaction vessel was charged with nitrogen. Palladium (10% on carbon) (0.30 g, 30%) was added to the solution. The mixture was hydrogenated for 3 h at room temperature. The palladium was filtered off through a celite pad. The filtrate was concentrated to give 0.79 g (85%) of the desired 4-[3-(trifluoromethoxy)phenyl]-butan-2-one as a yellow oil. ESMS m/z=232 [M+H]⁺.

EX-626C) In a flask equipped with a stir bar and molecular sieves, a solution of 3-phenoxyaniline (1.1 g, 0.0059 mol) in 15 mL of cyclohexane was prepared under nitrogen. A solution of the ketone (1.3 g, 0.006 mol) product from EX-626B dissolved in 5 mL of cyclohexane was added. The mixture was refluxed for 18 h, filtered and concentrated to give the desired imine product as a dark yellow oil. ESMS m/z=400 [M+H]⁺.

EX-626D) The imine product (1.3 g, 0.003 mol) from EX-626C was stirred with 5 mL of methanol at 0° C. Sodium borohydride (0.23 g, 0.005 mol) was added to the mixture, and the mixture was stirred at room temperature for 18 h. The mixture was acidified with 4 mL of 3% HCl and extracted with diethyl ether. The ether layers were combined, dried over MgSO₄ and concentrated to give 1.07 g (81%) of the desired 3-[1-methyl-3-[3-(trifluoromethoxy)phenyl]propyl](3-phenoxyphenyl)amine product as an orange oil. ESMS m/z=402 [M+H]⁺.

The 3-[1-methyl-3-[3-(trifluoromethoxy)phenyl]propyl](3-phenoxyphenyl)amine (1.0 g, 0.002 mol) product from EX-626D and 1,1,1-trifluoro-2,3-epoxypropane (0.56 g, 0.005 mol) were heated at 90° C. for 18 h. Excess epoxide was evaporated. The crude product was purified by flash column chromatography on silica gel eluting with 1:13 ethyl acetate in hexane to give 0.16 g (13%) of the desired 3-[[1-methyl-3-[3-(trifluoro-methoxy)phenyl]propyl](3-phenoxyphenyl)amino]-1,1,1-trifluoro-2-propanol product as a yellow oil. Anal calcd. for C₂₆H₂₅NO₃F₆: C, 60.82; H, 4.91; N, 2.72. Found: C, 60.63; H, 4.89; N, 2.70. HRMS calcd. 514.1816 [M+H]⁺, found: 514.1789. ¹H NMR (C₆D₆) δ7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46(dd, 1H), 6.38 (dd, 1H), 6.35 (t, H), 4.18 (m, 1H), 3.78 (m, 1H), 3.52 (dd, 1H), 3.28 (m, 1H), 2.76,(s, 1H), 2.53 (m, 2H), 1.92 (m, 1H), 1.63 (m, 1H), 1.24 (m, 3H). ¹⁹ F NMR (CDCl₃) δ−56.84 (s, 3F), −79.0 (s, 3F).

EXAMPLE 627

3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]methoxymethylbenzene

EX-627A) A suspension of N-bromosuccinimide (17.6 g, 0.099 mol) in carbon tetra-chloride was added to a stirring solution of m-xylene in carbon tetrachloride. Then 2,2-azobisisobutyronitrile catalyst (0.71 g, 0.004 mol) was added. The resulting mixture was refluxed for 2 h, then quenched with 50 mL of water. The organic layer was collected, washed with water followed by brine, dried over MgSO₄ and concentrated to give 2.0 g (16%) of the desired crude 1,3-dibromoxylene product. ESMS m/z=264 [M+H]⁺.

EX-627B) The 1,3-dibromoxylene (2.0 g, 0.0076 mol) from EX-627A and sodium methoxide (2.45 g, 0.045 mol) were mixed in 25 mL of MeOH. The resulting mixture was stirred at room temperature for 18 h, concentrated, dissolved in methylene chloride and washed with water. The organic layer was further washed with brine and dried over MgSO₄ and concentrated to give 0.912 g (72%) of the desired 1,3-di-(methoxy-methyl)benzene product as a yellow oil. ESMS m/z=166 [M+H]⁺.

EX-627C) The diether product (0.90 g, 0.0054 mol) from EX-627B was stirred in a mixture of 10:1 methylene chloride:water. To this was added 2,3-dichloro-5,6dicyano-benzoquinone (1.84 g, 0.0081 mol). The resulting biphasic mixture was stirred at room temperature for 72 h. The mixture was then washed with saturated sodium bicarbonate followed by brine, dried over MgSO₄ and concentrated. The crude product was purified by flash column chromatography on silica eluting with 1:4 ethyl acetate:hexane to give 0.430 g (53%) of the desired 3-(methoxymethyl)benzaldehyde product as a pink oil. ¹H NMR (CDCl₃) δ10.00 (s, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.63 (d, 1H), 7.51 (t, 1H), 4.58 (s, 2H), 3.40 (s, 3H).

EX-627D) The 3-(methoxymethyl)benzaldehyde (0.430 g, 2.87 mmol) from EX-627C was added to a stirring solution of 3-phenoxyaniline (0.530 g, 2.87 mmol) in 5 mL of dichloromethane. Then sodium triacetoxyborohydride (0.670 g, 3.16 mmol) was added followed by acetic acid (0.196 g, 3.27 mmol). The resulting mixture was stirred at room temperature 18 h, then diluted in methylene chloride and quenched with sodium bicarbonate. The organic layer was washed with brine, dried over MgSO₄ and concentrated to give 0.870 g (95%) of the desired N-3-(phenoxyphenyl)-[[3-(methoxy-methyl)phenyl]methyl]amine product as a pink oil. ESMS m/z=3201 [M+H]⁺.

The N-3-(phenoxyphenyl)-[[3-(methoxymethyl)phenyl]methyl]amine product (0.87 g, 0.003 mol) from EX-627D was mixed with 1,1,1-trifluoro-2,3-epoxypropane (0.61 g, 0.005 mol) in a pressurized vial. A suspension of ytterbium triflate (0.16 g, 0.272 mmol) in 0.5 mL of acetonitrile was added. The resulting mixture was stirred at room temperature for 18 h, then quenched with water and extracted with ethyl acetate. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate:hexane to give 0.35 g (30%) of the desired 3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]methoxymethylbenzene product as a pure yellow oil. Anal calcd. for C₂₄H₂₄NO₃F₃.0.5 H₂O: C, 65.18; H, 5.61; N, 3.17. Found: C, 65.19; H, 5.36; N, 3.13. HRMS calcd. 432.1786 [M+H]⁺, found: 432.1803. ¹H NMR (C₆D₆) δ6.82 (m, 7H), 6.60 (dd, 1H), 6.42 (dd, 1H), 6.38 (s, 1H), 6.18 (dd, 1H), 4.00 (s, 2H), 3.63 (m, 1H), 3.40 (d, 1H), 3.02 (m, 1H), 1.80 (d, 1H). 19F NMR (C₆D₆) δ−78.55 (s, 3F).

EXAMPLE 628

3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol

EX-628A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbon tetrachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixture was refluxed for 2 h then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO₄, and concentrated in vacuo to give 66.0 g (96%) of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil. ¹H NMR indicates that this oil is a mixture of products: 7% dibrominated, 67% monobrominated, and 20% starting material. The crude product was used without further purification. ESMS m/z=287 [M+H]⁺.

EX-628B) The crude product (56 g,0. 14 mol) from EX-628A in 200 mL of cyclohexane was added dropwise under nitrogen to a solution of 3-phenoxyaniline (89 g,0.480 mol) in 500 mL of cyclohexane. The reaction mixture was refluxed overnight, then cooled to room temperature and diluted with water and diethyl ether. The layers were separated, and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give a dark oil. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 44.96 g (83%) of the desired N-3-(phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a yellow oil. ESMS m/z=392 [M+H]⁺.

To a mixture of the amine product (15.0 g, 0.038 mol) from EX-628B and 1,1,1-tri-fluoro-2,3-epoxypropane (8.58 g, 0.077 mol) was added a suspension of ytterbium (III) trifluoromethanesulfonate (2.37 g. 0.0031 mol) in 15 mL of acetonitrile. The resulting mixture was heated at 50° C. in a sealed glass vial for 1.5 h. The reaction mixture was cooled to room temperature then diluted with water and ethyl acetate and extracted. The organic layers were combined, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 12.03 g (62%) of the desired 3-[(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil. Anal. calcd. for C₂₄H₂₀F₇NO₃: C, 57.26; H, 4.00; N, 2.78. Found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd. 504.1410 [M+H]⁺, found: 504.1431. ¹H NMR (CDCl₃) δ7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ−79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).

EXAMPLE 629

3-[[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-629A) 3-Aminophenol (5 g, 46 mmol), 1-bromo-2,4-difluorobenzene (10 g, 50 mmol) and Cs₂CO₃ (16 g. 50 mmol) were mixed in 25 mL of dimethylformamide. Solid (CuOTf)₂C₆H₆ (100 mg) was added, and the mixture was stirred under nitrogen at 85° C. for 22 h, at which time HPLC analysis indicated that the reaction had gone to completion and formed two products. The DMF was removed under reduced pressure. The residue was diluted with ether and filtered through a celite pad. The pad was washed with ether and a small amount of water. The mixture was extracted with ether several times. The combined ether layers were washed with water and brine, then dried over MgSO₄. The dried organic layer was evaporated to give 10.2 g (80%) of the desired product, which consisted of a 11:1 ratio of 3-(2-bromo-5-fluorophenoxy)-aniline and 3-(4bromo-3-fluorophenoxy)aniline. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 8.8 g (68%) of the desired product as a yellow oil, which was a 25:1 ratio of 3-(2-bromo-5-fluorophenoxy)aniline and 3-(4-bromo-3-fluorophenoxy)aniline. HRMS calcd. for C₁₂H₉NOFBr: 281.9930 [M+H]⁺, found: 281.9950.

EX-629B) The crude 3-(2-bromo-5-fluorophenoxy)aniline (1.39 g, 4.95 mmol) product from EX-629A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.0 g 4.5 mmol) were dissolved in 15 mL of dichloroethane and acetic acid (0.30 mL, 5.4 mmol), then solid NaBH(OAc)₃ (1.26 g, 5.9 mmol) was added. The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄, and evaporated to give 2.1 g (97%) of crude product, which was purified by flash column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 2.0 g (91%) of the desired 3-[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amine product, as a light yellow oil, >90% pure by HPLC analysis. HRMS calcd. for C₂₁H₁₅NO₂BrF₅: 488.0285 [M+H]⁺, found: 488.0269.

The 3-[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine (0.97 g, 2.0 mmol) product from EX-629B and 1,1,1-trifluoro-2,3-epoxypropane (0.45 g, 4.0 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.12 g, 0.2 mmol) was added. and the stirred solution was warmed to 40° C. for 1 h, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 0.83 g (69%) of the desired 3-[[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol product as a clear colorless oil, >95% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.50 (dd, 1H), 7.30 (t, 1H), 7.18 (t, 1H), 7.07 (t, 2H), 6.99 (s, 1H), 6.70 (dt, 1H), 6.56 (dd, 1H), 6.52 (dd, 1H), 6.38 (dd, 1H), 6.32 (m, 1H), 5.87 (tt, 1H), 4.65 (d, 2H), 4.33 (m, 1H), 3.85 (dd, 1H), 3.56 (dd, 1H), 2.48 (bs, 1H). NOE difference spectra confirmed that the isolated material was the indicated N-[3-(2-bromo-5-fluorophenoxy)phenyl]-3-aminopropanol product. ¹⁹F NMR (CDCl₃) δ−79.24 (d, 3F), −88.57 (m, 2F), −112.04 (q, 1H), −137.16 (dt, 2F). Anal. calcd. for C₂₄H₁₈NO₃BrF₈: C, 48.02; H, 3.02; N, 2.33. Found: C, 48.48; H, 3.18; N, 2.33. HRMS calcd. 600.0420 [M+H]⁺, found: 600.0415.

EXAMPLE 630

3-[[3-(-5-bromo-2-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-630A) 3-Aminophenol (5 g, 46 mmol), 1-bromo-3,4-difluorobenzene (10 g, 50 mmol) and Cs₂CO₃ (16 g, 50 mmol were mixed in 25 mL of DMF. Solid (CuOTf)₂C₆H₆ (100 mg) was added, and the mixture was stirred under nitrogen at 85° C. for 22 h, at which time HPLC analysis indicated that the reaction had gone to completion and formed two products. The DMF was removed under reduced pressure. The residue was diluted with ether and filtered through a celite pad. The pad was washed with ether and a small amount of water. The mixture was extracted with ether several times. The combined ether layers were washed with water and brine, then dried over MgSO₄. The dried organic layer was evaporated to give 7.5 g (58%) of the desired products, which comprised a 10:1 ratio of 3-(5-bromo-2-fluorophenoxy)aniline and 3-(4-bromo-2-fluorophenoxy)aniline. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 4.5 g (35%) of the desired products as a yellow oil, which were a 20:1 ratio of 3-(5-bromo-2-fluorophenoxy)aniline and 3-(4bromo-2-fluorophenoxy)aniline. HRMS calcd. for C₁₂H₉NOFBr: 281.9930 [M+H]⁺, found 281.9951.

EX-630B) The crude 3-(5-bromo-2-fluorophenoxy)aniline (1.39 g, 4.95 mmol) product from EX-630A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.0 g, 4.5 mmol) were dissolved in 15 mL of dichloroethane and acetic acid (0.30 mL, 5.4 mmol), then solid NaBH(OAc)₃ (1.26 g, 5.9 mmol) was added. The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄, and evaporated to give 2.1 g (97%) of crude product, which was purified by flash column chromatography on silica gel eluting with 1:7 ethyl acetate:hexane to give 2.0 g (91%) of the desired 3-[3-(5-bromo-2-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product, as a yellow oil, >95% pure by HPLC analysis. Anal. calcd. for C₂₁H₁₅NO₂BrF₂: C, 51.66; H, 3.10; N, 2.87. Found: C, 51.90; H, 3.08; N, 2.86. HRMS calcd. 488.0284 [M+H]⁺, found 488.0281.

The amine (1.1 g, 2.26 mmol) product from EX-630B and 1,1,1-trifluoro-2,3-epoxypropane (0.38 g, 3.39 mmol) were dissolved in 1 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.14 g, 0.23 mmol) was added, and the stirred solution was warmed to 40° C. for 1 h, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with 1:7 ethyl acetate:hexane to give 0.5 g (37%) of the desired 3-[[3-(5-bromo-2-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1,-tri-fluoro-2-propanol product as a yellow oil, >95% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.50 (t, 1H), 7.20 (dd, 1H), 7.17 (dd, 1H), 7.17 (dd, 1H), 7.09 (t, 2H), 7.00 (dd, 2H), 6.52 (dd, 1H), 6.38 (dd, 1H), 6.37 (s, 1H), 5.87 (tt, 1H), 4.64 (s, 2H), 4.33 (m, 1H), 3.85 (dd, 1H), 3.56 (dd, 1H). ¹⁹F NMR (CDCl₃) δ−79.20 (d, 3F), −88.55 (m, 2F), −113.04 (m, 1H), −137.05 (dt, 2F). NOE difference and pcosy spectra confirmed that the isolated material was the indicated N-[3-(5-bromo-2-fluorophenoxy)phenyl]-3-aminopropanol product. Anal. calcd. for C₂₄H₁₈NO₃BrF₈: C, 48.02; H, 3.02; N, 2.33. Found: C, 48.07: H, 3.14: N, 2.31. HRMS calcd. 600.0420 [M+H]⁺, found: 600.0404.

EXAMPLE 631

3-[(3-phenoxyphenyl)[[4-(N,N-diethylamino)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

4 EX-631A) The 3-phenoxyaniline aniline (0.74 g, 4.0 mmol) and 4-(N,N-diethylamino)benzaldehyde (0.59 g, 3.3 mmol) were dissolved in 10 mL of dichloroethane and acetic acid (0.22 mL, 4.0 mmol). Then solid NaBH(OAc)₃ (0.94 g, 4.4 mmol) was added. The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄, and evaporated to give 1.3 g of crude product, which was purified by flash column chromatography on silica gel eluting with 1:7 ethyl acetate:hexane to give 1.0 g (87%) of the desired 3-[(3-phenoxyphenyl)[4-(N,N-diethylamino)phenyl]methyl]-amine product. HRMS calcd. for C₂₃H₂₆ N₂O: 347.2123 [M+H]⁺, found 347.2124.

The 3-[(3-phenoxyphenyl)[4(N,N-diethylamino)phenyl]methyl]amine (0.69 g, 2.0 mmol) product from EX-631A and 1,1,1-trifluoro-2,3-epoxypropane (0.45 g, 4 mmol) were dissolved in 1 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.12 g, 0.1 mmol) was added, and the stirred solution was warmed to 40° C. for 4 h, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 ethyl acetate:hexane:ammonium hydroxide followed by reverse phase preparative HPLC eluting with 10% to 90% acetonitrile in water to give 160 mg (17%) of the desired 3-[(3-phenoxyphenyl)-[[4-(N,N-diethylamino)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, >95% pure by HPLC analysis. ¹H NMR (CD₃OD) δ7.39 (d, 2H), 7.31 (d, 2H), 7.22 (m, 3H), 7.13 (d, 1H), 6.98 (t, 1H), 6.75 (dd, 2H), 6.47 (dd, 1H), 6.20 (d, 1H), 4.03 (m, 1H), 3.90 (s, 2H), 3.58 (m, 4H), 3.36 (dd, 1H), 3.12 (dd, 1H), 1.05 (t, 6H). ¹⁹F NMR (CD₃OD) δ−80.51 (d, 3F). HRMS calcd. 459.2259 [M+H]⁺, found: 459.2250.

EXAMPLE 632

N-[2-chloro-6-(p-fluorophenoxy)-1,3,5-triazin-4-yl]-3-[[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-632A) 3-Trifluoromethoxybenzenemethanamine (1.15g, 6 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (0.67 g, 6 mmol) were combined and stirred at 80° C. for 1.5 h. The mixture was cooled to room temperature, and the resulting solid was recrystallized from hot hexanes. The white solid was isolated by vacuum filtration and washed with cold hexanes to give 0.67 g (37%) of pure 3-[[[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol. ¹H NMR (CDCl₃) δ7.37 (t, 1H), 7.24 (d, 1H), 7.15 (m, 2H), 3.99 (m, 1H), 3.85 (d, 2H), 2.98 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 1H). ¹⁹F NMR (CDCl₃) δ−58.19 (s, 3F), −78.88 (s, 3F). HRMS calcd. for C₁₁H₁₁F₆NO₂: 304.0772 [M+H]⁺, found: 304.0794.

EX-632B) To a solution of 4-fluorophenol 1.00 g (8.92 mmol) in 30 mL of tetrahydrofuran at 0° C. was added a 60% dispersion of sodium hydride in mineral oil (0.36 g, 8.92 mmol). After 30 min, cyanuric chloride (1.64 g, 8.92 mmol) was added as a heterogeneous mixture in tetrahydrofuran at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After 14 h, the mixture was cooled to 0° C. and a saturated aq. NH₄Cl solution was added. The aqueous solution was extracted with diethyl ether (3×50 mL). The combined ether extracts were washed with brine, dried (MgSO₄), and concentrated in vacuo to afford 1.34 g (58%) of the desired 2,4-dichloro-6-(4-fluorophenoxy)-1,3,5-triazine product as an off white solid which was taken on to the next step without purification. MS m/z=260 [M+H]⁺.

To a stirred solution of aminopropanol from EX-632A (0.100 g, 0.330 mmol) in N,N-dimethylformamide at 0° C. was added the 2,4dichloro-(4-fluorophenoxy)-1,3,5-triazine ether product from EX-632B (0.086 g, 0.330 mmol) as a solution in N,N-di-methylformamide. The reaction mixture was allowed to slowly warm to room temperature. After 14 h, the reaction mixture was cooled to 0° C. and a saturated aq. NaHCO₃ solution was added. After stirring the reaction mixture for 30 min at room temperature, the aqueous layer was extracted with ether (3×30 mL). The combined ether extracts were washed with brine, dried (MgSO₄), and concentrated in vacuo to give a yellow oil. The crude residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexanes to give 0.075 g (43%) of the desired N-[2-chloro-6-(p-fluorophenoxy)-1,3,5-triazin-4-yl]-3-[[[3-(trifluoromethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol product as a pale yellow oil. HRMS calcd. for C₂₀H₁₄CIF₇N₄O₃: 526.0643 [M⁺], found: 526.0632. ¹H NMR (C₆D₆) δ6.95 (s, 1H), 6.63 (m, 14H), 4.74 (d, 1H), 4.37 (d, 1H), 4.16 (d, 1H), 4.00 (d, 2H), 3.73 (m, 1H), 3.48 (m, 2H), 3.26 (m, 2H), 3.12 (m, 2H).

EXAMPLE 633

3-[[3-(2-methyl-5-pyridyloxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol

EX-633A) 3-Bromoaniline (2.15 g, 12.5 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (1.0 g, 8.9 mmol) were placed in a sealed vial, heated to 70° C. and stirred for 1 h under an atmosphere of nitrogen. The crude product was purified by flash column chromatography on silica gel eluting with CH₂CH₂:hexane (2:1) to give 2.11 g (84%) of the desired 3-[(3-bromophenyl)amino]1,1,1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. MS m/z=284/286 [M+H]⁺.

EX-633B) The 3-[(3-bromophenyl)amino]-1,1,1-trifluoro-2-propanol (1.14 g, 4 mmol) from EX-633A and 3-(trifluoromethoxy)benzaldehyde (0.78 g, 4.1 mmol) were dissolved in dichloroethane (18 mL). Acetic acid (0.253 mL, 4.2 mmol) and solid NaBH(OAc)₃ (1.07 g, 5.05 mmol) were added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCl solution. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO₄, and evaporated to give 1.12 g (62%) of the desired N-3-bromophenyl-[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,]-trifluoro-2-propanol product as a brown oil, which was greater than 80% pure by reverse phase HPLC analysis. HRMS calcd. for C₁₇H₁₄NO₂F₆Br. 458.0190 [M+H]⁺, found: 458.0199.

The 3-[(3-bromophenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (500 mg, 1.1 mmol) product from EX-633B and 5-hydroxy-2-methylpyridine (262 mg, 2.4 mmol) were dissolved in dimethylacetamide (6 mL). Cs₂CO₃ (1.0 g, 3.1 mmol) and (CuCF₃SO₃)₂C₆H₆ (150 mg) were added, and the mixture was heated to 105° C. for 96 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that most of the starting materials had been consumed. After adding water, the reaction mixture was extracted with ether, and the ether extracts were washed with brine and dried over anhydrous MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:12) to give 326 mg (61%) of the desired 3-[[3-(2-methyl-5-pyridyloxy)phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 99% pure by HPLC analysis. ¹H NMR (CDCl₃) δ8.00 (s, 1H), 7.29 (t 1H), 6.99 (s, 1H), 7.02-7.15 (m, 5H), 6.46 (dd, 1H), 6.29 (t, 1H), 6.25 (dd, 1H), 4.88 (br s, 1H), 4.67 (ABq, 2H), 4.36 (m, 1H), 3.88 (dd, 1H), 3.56(dd, 1H), 2.49 (s, 3H). ¹⁹F NMR (CDCl₃) δ−58.2, (s, 3F), −79.1 (d, 3F). HRMS calcd. for C₂₃H₂₀N₂O₃F₆: 487.1456 [M+H]⁺, found: 487.1425.

EXAMPLE 634

3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-634A) Dinitrobenzene (1.68 g, 10 mmol) and 4-fluorophenol (1.13 g, 10 mmol) were dissolved in anhydrous dimethylsulfoxide (25 mL), and powdered cesium carbonate (8 g, 24.8 mmol) was added. The mixture was stirred and heated to 100° C. using a reflux condenser under a nitrogen atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4×60 mL). The combined ether layers were washed with 3% HCl, 5% sodium hydroxide, and water, then dried over anhydrous MgSO₄. The ether was removed in vacuo, and the recovered oil was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:25) to give 1.68 g (69%) of the desired 3-(4-fluorophenoxy)nitrobenzene product as orange crystals, 97% pure by HPLC analysis. MS m/z=234 [M+H]⁺.

EX-634B) 3-(4-Fluorophenoxy)nitrobenzene (1.15 g, 4.93 mmol) from EX-634A was dissolved in ethanol (45 mL), and the solution was hydrogenated for 4 h in the presence of 5% palladium on charcoal. After the mixture was filtered through celite, the ethanol was removed in vacuo. The product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:10) to give 0.92 g (90%) of 3-(4-fluorophenoxy)aniline as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C₁₂H₁₁FNO: 204.0824 [M+H]⁺, found: 204.0837.

EX-634C) The 3-(4-fluorophenoxy)aniline (812 mg, 4 mmol) from EX-634B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (888 mg, 2 mmol) were dissolved in dichloroethane (15 mL) and acetic acid (0.25 mL, 4.2 mmol), then solid NaBH(OAc)₃ (1.01 g, 5 mmol) was added. The mixture was stirred at room temperature for 3 h, then acidified with ¹N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO₄, and evaporated to give 1.32 g (78%) of the desired of N-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=410 [M+H]⁺.

The N-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine (612 mg, 1.5 mmol) product from EX-634C and 1,1,1-trifluoro-2,3-epoxypropane (268 mg, 2.4 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43 mg, 0.07 mmol) was added, and the stirred solution was warmed to 40° C. for 2.5 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO₄. The ether was removed in vacuo, and the crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:11) to give 633 mg (81%) of the desired 3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.35 (t, 1H), 7.15 (m, 3H), 6.98 (m, 5H), 6.49 (dd, 1H), 6.38 (dd, 1H), 6.33 (m, 1H), 5.92 (tt, 1H), 4.67 (ABq, 2H), 4.37 (m, 1H), 3.91 (dd, 1H), 3.59 (dd, 1H), 2.48 (d, 1H). ¹⁹F NMR (CDCl₃) δ−79.2 (d, 3F), −88.5 (m, 2F), −120.33 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C₂₄H₁₉F₈NO₃: 522.1315 [M+H]⁺, found: 522.1297.

Additional examples 3-[(aryloxyphenyl)[[phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 39 and 40.

Example Table 39. 3-[(aryloxyphenyl)[[phenyl]methyl]amino]- 1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB1) R_(SUB2) Mass [M + H]⁺ Mass [M + H]⁺ 635 4-F 3-OH 422.1379 422.1396 636 4-F 3-SCF₃ 505.0946 505.0927 637 4-CH₃ 3-SCF₃ 502.1275 502.1261 638 3,4-F₂ 3-OCF₂CF₂H 540.1221 540.1248 639 2,4-F₂ 3-OCF₂CF₂H 540.1221 540.1194 640 4-F 4-CF₃ 474.1304 474.1300

Example Table 40. 3-[[(3-aryloxy)-5-(trifluoromethyl)phenyl][[phenyl] methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB1) R_(SUB2) Mass [M + H]⁺ Mass [M + H]⁺ 641 4-F 3-CF₃ 542.1178 542.1205 642 4-F 3-SCF₃ 574.0898 574.0899 643 4-F 3-OCF₃ 558.1127 558.1137 644 4-F 3-OCF₂CF₂H 590.1189 590.1212

EXAMPLE 645

3-[(3-phenoxyphenyl)[[3-(isopropoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-645A) 3-Hydroxybenzaldehyde (5.60 g, 45.9 mmol) and 2-iodopropane (7.86 g, 46.2 mmol) were dissolved in 50 mL of isopropanol. Potassium carbonate (20 g, 145 mmol) was added, and the mixture was heated to reflux for 8 h, at which time TLC analysis indicated that the reaction had gone to completion. Water was added to dissolve all solids, and the mixture was extracted with ether (3×). The combined ether layer was washed with water, 2 M NaOH, again with water until clear (4×), and finally with brine. The solution was dried over MgSO₄, filtered, and evaporated to give 5.03 g (67%) of the desired 3-isopropoxybenzaldehyde product as a pale oil. ¹H NMR (C₆D₆) δ9.62 (s, 1H), 7.29 (s, 1H), 7.03 (m, 1H), 6.91 (t, 1H), 6.84 (m, 1H), 4.03 (septet, 1H), 0.96 (d, 6H).

EX-645B) The 3-isoproxybenzaldehyde (0.780 g, 4.75 mmol) product from EX-645A and 3-phenoxyaniline (0.881 g, 4.76 mmol) were combined in 20 mL of methanol, then solid NaCNBH₃ (0.238 g, 3.79 mmol) was added, and the mixture was stirred until uniform. Acetic acid (2 ml) was added, and the mixture was stirred at room temperature overnight, then quenched with water, made basic with potassium carbonate, and extracted with ether (3×). The combined ether layers were washed with water and brine, dried over MgSO₄, filtered, and evaporated to give 1.32 g (84%) of the desired N-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine product as an amber oil. ¹H NMR (C₆D₆) δ6.6-7.1 (m, 10H), 6.44 (m, 1H), 6.25-6.00 (dd, 1H), 6.15 (m, 1H), 4.25 (s, 1H), 4.19 (m, 1H), 3.80 (s, 1H), 2.65 (s, 1H), 1.07 (m, 6H). MS m/z=333 [M⁺].

The N-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine (0.528 g, 1.59 mmol) product from EX-645B and 1,1,1-trifluoro-2,3-epoxypropane (0.506 g, 4.51 mmol) were heated to 90° C. in a sealed container for 2 d under an argon atmosphere. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (0-10% ethyl acetate) and fractions were pooled after TLC analysis to give 197 mg (28%) of the desired 3-[(3-phenoxyphenyl)[[3-(isopro-poxy)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol product as clear, colorless oil. HRMS calcd. for C₂₅H₂₆F₃NO₃: 446.1943 [M+H]⁺, found: 446.1936. ¹H NMR (C₆D₆) δ6.9-7.1 (m, 6H), 6.84 (tt, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 6.61 (d, 1H), 6.56 (t, 1H), 6.41 (td, 2H), 4.33 (s, 2H), 4.17 (septet, 1H), 3.91 (br s, 1H), 3.56 (dd, 1H), 3.31 (m, 1H,), 2.8 (br s, 1H). 1.06 (s, 6H). ¹⁹F NMR (C₆D₆) δ−78.85 (d, 3F).

Additional examples of 3-[aryloxyphenyl[[3-aryl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 41.

Example Table 41. 3-[aryloxyphenyl[[3-aryl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. R_(SUB1) R_(SUB2) Mass [M + H]⁺ Mass [M + H]⁺ 646 F ethyl 450.1692 450.1682 647 F isopropyl 464.1849 464.1867 648 F n-propyl 464.1849 464.1820 649 F n-butyl 478.2005 478.2015 650 F sec-butyl 478.2005 478.1880 651 F —CH₂-cyclopropyl 476.1849 476.1857 652 F isobutyl 478.2005 478.1970 653 F cyclopentyl 490.2005 490.1998

EXAMPLE 654

3-[(3-phenoxyphenyl)[[3-(1,1-dimethylethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-654A) 3-Hydroxybenzaldehyde (4.08 g, 33.4 mmol) was slurried in 50 mL of anhydrous CH₂Cl₂ and added to t-butyl-2,2,2-trichloroacetimidate (25.0 g, 114 mmol) in 200 mL of anhydrous cyclohexane with an additional 50 mL of CH₂Cl₂ used in transfer. The mixture was stirred under nitrogen until uniform, then boron trifluoride diethyl etherate (0.50 mL, 4 mmol) was added via syringe and stirring was continued for 1 h. Powdered sodium bicarbonate (50 g, 0.6 mol) was added, and the solution was filtered through a silica gel plug, washing the plug with hexane. The solvent was evaporated to give crude product 3.54 g (59%) as an amber oil (85% pure by GC analysis). Chromatography on silica gel eluting with 0-10% ethyl acetate in hexane gave 1.88 g (32%) of pure 3-t-butoxybenzaldehyde product as a colorless oil. ¹H NMR (C₆D₆) δ9.59 (s, 1H), 7.44 (br s, 1H), 7.20 (d t, 1H), 6.92 (m, 2H), 1.07 (s, 9H).

EX-654B) The 3-t-butoxybenzaldehyde (0.585 g, 3.27 mmol) product from EX-654A and 3-phenoxyaniline (0.595 g, 3.21 mmol) were combined in 50 mL of THF, then solid NaBH(OAc)₃ (0.860 g, 4.06 mmol) was added, and the mixture was stirred until uniform. Acetic acid (0.2 g, 3.33 mmol) was added, and the mixture was stirred at room temperature for 4 h, then quenched with 5% aq. NaHCO₃. The aqueous layer was separated and extracted twice with ether. The combined ether layers were washed with water and brine, dried over MgSO₄, filtered, and evaporated to give 1.29 g (115%) of crude product as a brown oil. Chromatography on silica gel eluting with 0-10% ethyl acetate in hexane gave 464 mg (40%) of the desired N-(3-phenoxyphenyl)[[3-(1,1-dimethyl-ethoxy)phenyl]methyl]amine product as a colorless oil, pure by TLC. MS m/z=347 [M⁺].

The N-(3-phenoxyphenyl)[[3-(1,1,-dimethylethoxy)phenyl]methyl]amine (0.270 g, 0.78 mmol) product from EX-654B was dissolved in 2 mL of acetonitrile. Ytterbium triflate (16 mg, 0.026 mmol) was added in 0.5 mL of acetonitrile, and the mixture was stirred under nitrogen. 1,1,1-Trifluoro-2,3-epoxypropane (0.105 g, 0.94 mmol) was added, the vial was sealed and heated to 45° C. After 24 h, TLC analysis showed 50% conversion, so additional 1,1,1-trifluoro-2,3-epoxypropane (88.6 mg, 0.79 mmol) was added and heating continued for an additional 24 h. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (1.5-7% ethyl acetate). Fractions were pooled based on TLC analysis to give 150 mg (42%) of the desired 3-[(3-phenoxy-phenyl)[[3-(1,1-dimethylethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a clear, colorless oil, and an additional 60 mg (17%) was obtained as an amber oil. HRMS calcd. for C₂₆H₂₈F₃NO₃: 460.2100 [M+H]⁺, found: 460.2103. ¹H NMR (C₆D₆) δ6.78-7.08 (m, 9H), 6.68 (d, 1H), 6.55 (t, 1H), 6.43 (dd, 1H), 6.34 (dd, 1H), 4.23 (s, 2H), 3.81 (m, 1H), 3.48 (dd, 11H), 3.24 (m, 1H), 2.25 (br s, 1H), 1.07 (s, 9H). ¹⁹F NMR (C₆D₆) δ−78.92 (d, 3F).

EXAMPLE 655

3-[(3-phenoxyphenyl)[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-655A) The 3-(phenoxy)aniline (555 mg, 3 mmol) and 3-hydroxybenzaldehyde (366 mg, 3 mmol) were dissolved in 7 mL of 1,2-dichloroethane. Acetic acid (0.189 mL, 3.15 mmol) and solid NaBH(OAc)₃ (1.01 g, 5 mmol) were added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCl solution. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water. then dried over anhydrous MgSO₄, and evaporated to give 609 mg (69%) of the desired N-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=291.

The N-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine (400 mg, 1.35 mmol) product from EX-655A and 1,1,1-trifluoro-2,3-epoxypropane (348 mg, 3 mmol) were placed in a sealed vial, then stirred and heated to 95° C. for 15 h under an atmosphere of nitrogen. The vial was cooled, and more 1,1,1-trifluoro- 2,3-epoxypropane (112 mg, 1 mmol) was added. The vial was sealed, then stirred and heated to 95° C. for a further 20 h under an atmosphere of nitrogen. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:6) to give 518 mg (77%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.20-7.32 (m, 3H), 7.14 (t, 1H), 7.07 (t, 1H), 6.95 (d, 2H), 6.80 (m, 2H), 6.74 (s, 1H), 6.48 (dd, 1H), 6.38 (m, 2H), 4.59 (ABq, 2H), 4.31 (m, 1H), 4.18 (dd, 1H), 4.10 (dd, 1H), 3.83 (dd, 1H), 3.54 (dd, 1H), 2.92 (d, 1H), 2.61 (d, 1H). ¹⁹F NMR(CDCl₃) δ−78.0 (d, 3F), −79.2 (d, 3F). HRMS calcd. for C₂₅H₂₃F₆ NO₄: 516.1611 [M+H]⁺, found: 516.1618.

EX-655B) Another example, 3-[3-(4-fluorophenoxy)phenyl[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol, was prepared by a similar method using 3-(4-fluorophenoxy)aniline as the staring material. HRMS calcd. for C₂₅H₂₂F₇NO₄: 534.1515 [M+H]⁺, found: 534.1505.

EXAMPLE 656

3-[[3-(4-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-656A) 3-Aminophenol (5.0 g, 45.8 mmol) and 4bromo-α,α, α-trifluorotoluene (14.0 g, 62.2 mmol) were dissolved in anhydrous dimethylacetamide (20 mL), then anhydrous cesium carbonate (30 g, 92.3 mmol) and copper triflate benzene complex (200 mg) were added. The mixture was stirred and heated to 85° C. using a reflux condenser under an argon atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4×60 mL). The combined ether layers were washed with 3% HCl, 5% NaOH and water, then dried over anhydrous MgSO₄. The ether was removed in vacuo, and the recovered oil purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 6.8 g (59%) of the desired 3-(4-trifluoromethylphenoxy)aniline product as a yellow oil, which solidified to a yellow powder, 98% pure by HPLC analysis. HRMS calcd. for C₁₃H₁₀F₃NO: 254.0792 [M+H]⁺, found: 254.0798.

EX-656B) The 3-(4-trifluoromethylphenoxy)aniline (632 mg, 2.5 mmol) from EX-656A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (555 mg, 2.5 mmol) were dissolved in 6 mL of dichloroethane and glacial acetic acid (0.15 mL, 2.8 mmol), and solid NaBH(OAc)₃ (1.01 g, 5 mmol) was added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with CH₂Cl₂ (3×20 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO₄, and evaporated to give 861 mg (75%) of the desired N-3-(4-trifluoromethyl phenoxy)-phenyl[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=460 [M+H]⁺.

The N-3-(4-trifluoromethylphenoxy)-phenyl[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine (689 mg, 1.5 mmol) product from EX-656B and 1,1,1-trifluoro-2,3-epoxypropane (252 mg, 2.25 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43 mg, 0.07 mmol) was added, and the stirred solution was warmed to 50° C. for 2.5 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:12) to give 520 mg (61%) of the desired 3-[[3-(4-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.49 (d, 2H), 7.30 (t, 1H), 7.20 (t, 1H), 7.07 (m, 2H), 7.00 (s, 1H), 6.95 (d, 2H), 6.55 (dd, 1H), 6.43 (dd, 1H), 6.34 (t, 1H), 5.87 (tt, 1H), 4.64 (ABq, 2H), 4.33 (m, 1H), 3.88 (dd, 1H), 3.58 (dd, 1H), 2.43 (bs, 1H). ¹⁹F NMR (CDCl₃) δ−62.2 (s, 3F), −79.2 (d, 3F), −88.6 (m, 2F), −137.2 (dt, 2F). HRMS calcd. for C₂₅H₁₉F₁₀NO₃: 572.1282 [M+H]⁺, found: 572.1268.

Additional examples of 3-[aryloxyphenyl[[phenyl]methyl]amino]-1,1,1-tri-fluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 42.

Example Table 42. 3-[Aryloxyphenyl[[phenyl]methyl]amino]- 1,1,1-trifluoro-2-propanols

Calculated Observed Ex. Mass Mass No. R_(SUB1) [M + H]⁺ [M + H]⁺ 657 CN 529.1362 529.1364 658 OCF₃ 588.1233 588.1241

EXAMPLE 659

3-[(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-659A) 3-Hydroxybenzaldehyde (12.22 g, 0.10 mol) and 100 mL of anhydrous methanol were combined in a 250 mL round-bottom flask. Sodium methoxide was slowly added as a 25 wt. % solution in methanol (21.61 g, 0.10 mol), and the methanol was removed under vacuum. Then 2,2,2-trifluoroethyl-p-toluenesulfonate (25.42 g, 0.10 mol) was added, the flask was purged with nitrogen, and 100 mL of N-methyl pyrrolidine was added. The solution was stirred for 24 h at 90° C., quenched with water, and extracted with ether (3×). The combined ether layers were washed with 1 M NaOH (2×), water, and brine, dried over MgSO₄, filtered, and evaporated to give 11.72 g of crude product. Chromatography over silica gel eluting with 0-10% ethyl acetate in hexane followed by a second chromatography with toluene gave 5.24 g (26%) of the desired 3-(2,2,2-trifluoroethoxy)benzaldehyde product as a pale oil. ¹H NMR (C₆D₆) δ9.61 (s, 1H), 7.14 (d, 1H), 7.06 (s, 1H), 6.97 (t, 1H), 6.75 (m, 1H), 3.75 (m, 2H). ¹⁹F NMR (C₆D₆) δ−74.45 (t, 3F).

EX-659B) The 3-(2,2,2-trifluoroethoxy)benzaldehyde (0.360 g, 1.76 mmol) product from EX-659A and 3-phenoxyaniline (0.326 g, 1.76 mmol) were combined in 50 mL of cyclohexane with 3 Å molecular sieves (1 g) and stirred overnight at 80° C. The mixture was cooled, filtered, and evaporated, then dissolved in 50 mL of methanol and cooled to 0° C. Solid sodium borohydride (0.030 g, 0.79 mmol) was added in portionsm, and the mixture was stirred overnight. The reaction was quenched with 5% aq. NaHCO₃ and extracted with ether (3×). The combined ether layers were washed with water and brine, dried over MgSO₄, filtered, and evaporated to give 0.50 g (76%) of the desired N-(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine product as an amber oil, >95% pure by normal phase HPLC analysis. MS m/z=373 [M⁺].

The N-(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine (0.50 g, 1.35 mmol) product from EX-659B and 1,1,1-trifluoro-2,3-epoxy-propane (1.0 ml, 11 mmol) were heated to 90° C. in a sealed container under argon for 2 d. The resulting mixture was eluted from silica gel with 4% ethyl acetate in hexane, and fractions were pooled based on TLC analysis to give 134 mg (21%) of the desired 3-[(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a clear. colorless oil. ¹H NMR (C₆D₆) δ6.80-7.08 (m, 7H), 6.64 (d, 1H), 6.53 (bt. 1H), 6.49 (t, 1H), 6.44 (dd, 1H), 6.34 (dt, 2H), 4.23 (s, 2H), 3.84 (m, 1H), 3.61 (m, 2H), 3.53 (dd, 1H), 3.20 (m, 1H), 2.03 (d, 1H). ¹⁹F NMR (C₆D₆) δ−74.20 (t, 3F), −78.95 (d, 3F). HRMS calcd. for C₂₄H₂₁F₆NO₃: 486.1504 [M+H]⁺, found: 486.1498.

EXAMPLE 660

3-[(4-chloro-3-ethylphenoxy)phenyl[[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol

EX-660A) Sodium pentafluoroethyl propionate (8.4 g, 50 mmol) and 3-iodotoluene (5.5 g, 25 mmol) were dissolved in anhydrous DMF (300 mL). Cul (9.5 g, 50 mmol) was added, and the mixture was heated to 160° C. under nitrogen for 4 h, at which time a 15 mL fraction of a mixture of DMF and 3-pentafluoroethyl toluene was collected. The distillate was diluted with Et₂O and was washed with brine. The ether layer was dried over MgSO₄, filtered and concentrated in vacuo to give 5.25 g (55%) of the desired 3-pentafluoroethyl-toluene product as a colorless oil. ¹H NMR (CDCl₃) δ7.36 (m, 4H), 2.40 (s, 3H). ¹⁹F NMR (CDCl₃) δ−85.2 (s. 3F), −115.2 (s, 2F).

EX-660B) The 3-pentafluoroethyl-toluene (2.9 g, 13.8 mmol) product from EX-660A and N-bromosuccinimide (2.5 g, 13.8 mmol) were dissolved in CCl₄ (25 mL). AIBN (50 mg) was added. and the mixture was refluxed for 3.5 h under N₂. The reaction mixture was cooled to room temperature and diluted with water. The layers were separated, and the organic layer was washed with brine, dried with anhydrous MgSO₄, filtered, and concentrated in vacuo to give 3.4 g (87%) of a colorless oil. The ¹H NMR spectrum indicated that the crude product contained 3-pentafluoroethyl-benzylbromide (70%), the benzyl dibromide (10%) and 3-pentafluoroethyl toluene (20%). ¹H NMR (CDCl₃) δ7.60 (m, 2H), 7.50 (m, 2H), 4.50 (s, 2H). ¹⁹F NMR (CDCl₃) δ−85.1 (s, 3F), −115.4 (s, 2F).

EX-660C) A solution of 3-(4-chloro-3-ethylphenoxy)aniline (1.7g, 6.9 mmol) was prepared in cyclohexane (13 mL). A solution of crude 3-pentafluoroethyl benzylbromide (1 g, 3.5 mmol) product from EX-660B in cyclohexane (10 mL) was added dropwise over 3 min. The reaction mixture was refluxed under N₂ for 24 h and then was cooled to room temperature. The mixture was diluted with Et₂O and saturated aqueous NaHCO₃. The layers were separated, and the aqueous layer was extracted with Et₂O. The organic layer was washed with brine, dried with anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes in ethyl acetate (95:5) which gave 0.56 g (35%) of the desired N-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoro-ethyl)phenyl]methyl]amine product as an amber oil. ¹H NMR (CDCl₃) δ7.53 (m, 4H), 7.27 (d, 1H), 7.15 (t, 1H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.41 (tt, 2H), 6.30 (t, 1H), 4.41 (s, 2H), 2.73 (q, 2H), 1.23 (t, 3H). ¹³C NMR (CDCl₃) δ158.6, 156.1, 143.4, 141.3, 140.2, 131.3, 130.7, 130.4, 129.4, 128.1, 120.4, 117.8, 108.8. 103.9, 48.5, 27.5, 14.1. ¹⁹F NMR (CDCl₃) δ−85.1 (s, 3F), −115.2 (s, 2F). HRMS calcd. for C₂₃H₁₉CIF₅NO: 456.1154 [M+H]⁺, found: 456.1164.

The N-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amine (0.05 g, 0.11 mmol) product of EX-660C was dissolved in anhydrous acetonitrile (0.2 mL). 1,1,1-trifluoro-2,3-epoxypropane (0.1 g, 0.89 mmol) and Yb(OTf)₃ (7 mg, 0.001 mmol) were added, and the reaction mixture was stirred under N₂ at 45° C. After 3 h, the reaction mixture was cooled to room temperature and diluted with Et₂O and saturated aqueous NaHCO₃. The layers were separated and the aqueous layer was extracted with Et₂O. The ether layers were combined, washed with brine, dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The viscous oil was adsorbed onto silica gel and eluted with hexanes in ethyl acetate (95:5) which gave 20 mg (32%) of the desired 3-[(4-chloro-3-ethylphenoxy)phenyl[[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol product as a viscous, colorless oil. ¹H NMR (CDCl₃) δ7.47 (m, 4H), 7.23 (m, 3H), 6.90 (d, 1H), 6.72 (dd, 1H), 6.52 (d, 1H), 6.42 (m, 2H), 4.73 (s, 2H), 4.39 (m, 1H), 3.91 (dd, 1H), 3.58 (m, 2H), 2.73 (q, 2H), 2.57 (s, 1H), 1.22 (t, 3H). ¹⁹F NMR (CDCl₃) δ−79.2 (s, 3F), −84.9(s, 3F), −115.2 (s, 2F). HRMS calcd. for C₂₆H₂₂ClF₈NO₂: 568.1290 [M+H]⁺, found: 568.1314.

EXAMPLE 661

6-fluoro-3,4-dihydro-4-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(trifluoromethyl)-2H-1,4-benzoxazine

EX-661A) A mixture of 2,5-difluoroaniline (2.58 g, 20 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (4.44 g, 20 mmol) in cyclohexane (50 mL) was heated under reflux for 5 h using a Dean-Stark trap to remove water. The solvent was removed in vacuo, and the residue was dissolved in methanol (30 mL). The solution was stirred and cooled to 0° C., then sodium borohydride was added (1.32 g, 35 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h, then acidified with 1 N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with diethyl ether (3×20 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO₄, and evaporated to give 5.7 g (86%) of the desired N-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=336 [M⁺].

EX -661B) The N-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amine (2.22 g, 6.67 mmol) product from EX-661A and 1,1,1-trifluoro-2,3-epoxypropane (1.12 g, 10 mmol) were dissolved in 1.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.21 g, 0.33 mmol) was added, and the stirred solution was warmed to 50° C. for 2 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over anhydrous MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:10) to give 2.49 g (84%) of the desired 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C₁₈H₁₄F₉NO₂: 448.0959 [M+H]⁺, found: 448.0940.

The 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.45 mmol) product from EX-661B was dissolved in anhydrous dimethylformamide (20 mL), and powdered K₂CO₃ (180 mg) was added. The mixture was stirred and heated to 145° C. for 15 h. The mixture was diluted with water (60 mL) and extracted into ether (2×40 mL), which was washed with brine and water. The ether solution was dried over anhydrous MgSO₄, and the ether was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:15) to give 86.9 mg (48%) of the desired 6-fluoro-3,4-dihydro[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(tri-fluoromethyl)-2H-1,4-benzoxazine product as a yellow oil, 98% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.39 (t, 1H), 7.17 (m, 3H), 6.88 (m, 1H), 6.41 (m, 2H), 5.92 (tt, 1H), 4.54 (m, 1H), 4.45 (s, 2H), 3.44 (m, 2H). ¹⁹F NMR (CDCl₃) δ−77.7 (d, 3F), −88.6 (m, 2F), −120.28 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C ₁₈H₁₃F₈NO₂: 428.0899 [M+H]⁺, found: 428.0910.

EXAMPLE 662

2,2,2-trifluoro-1-[[(3-fluorophenyl)[3-(trifluoromethyl)benzoyl]amino]-methyl]ethyl 3-trifluoromethylbenzoate

EX -662A) 3-[(3-fluorophenyl)[phenylmethyl]amino]-1,1,1,-trifluoro-2-propanol (2.56 g, 8.2 mmol) was dissolved in methanol (30 mL) and hydrogenated over 5% palladium on charcoal for 3 h. The mixture was filtered through celite, and the solvent was removed in vacuo to give 1.8 g (98%) of the desired 3-[(3-fluorophenyl)amino]-1,1,1-trifluoro-2-propanol product as an oil, 99% pure by HPLC analysis. MS m/z=224 [M+H]⁺.

The 3-[(3-fluorophenyl)amino]-1,1,1-trifluoro-2-propanol (446 mg, 2.0 mmol) from EX-662A and triethylamine (544 mg) were dissolved in anhydrous CHCl₃ (30 mL) and cooled to 0° C. Then a solution of 3-trifluoromethylbenzoyl chloride (1.04 g, 5.0 mmol) in anhydrous CHCl₃ (6 mL) was added over a period of 15 min. The solution was stirred at room temperature. After 14 h, the solution was washed with 5% NaHCO₃ (2×20 mL) and brine (2×10 mL), and then dried over anhydrous MgSO₄. Removal of the solvent in vacuo gave 832 mg (73%) of the desired 2,2,2-trifluoro-1-[[(3-fluoro-phenyl)[3-(trifluoromethyl)benzoyl]amino]methyl]ethyl 3-trifluoromethyl-benzoate product as an amber oil, which was greater than 95% pure by reverse phase HPLC analysis. ¹H NMR (CDCl₃) δ7.25-8.39 (m, 9H), 7.02 (q, 1H), 6.71 (m, 2H), 6.11 (m, 1H), 4.58 (dd, 1H), 4.35 (dd, 1H). ¹⁹F NMR (CDCl₃) δ−64.4 (m, 6F), −77.4 (s, 3F), −111.3 (m, 1F). HRMS calcd. for C₂₅H₁₅F₁₀NO₃: 568.0970 [M+H]⁺, found: 568.0968.

EXAMPLE 663

N-(3-fluorophenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-3-(trifluoromethyl)benzamide

A solution of 2,2,2-trifluoro-1-[[(3-fluorophenyl)[3-(trifluoromethyl)benzoyl]amino]-methyl]ethyl 3-trifluoromethyl-benzoate (600 mg, 1.06 mmol) from EX-662 in methanol was treated with 28% ammonia solution (122 μL). The solution was stirred at room temperature for 10 h. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 255 mg (61%) of the desired N-(3-fluorophenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-3-(trifluoromethyl)benzamide product as a white powder, 97% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.56 (m, 3H), 7.32 (m 2H), 6.98 (m, 1H), 6.90 (m, 2H), 4.49 (dd, 1H), 4.34 (d, 1H), 4.26 (m, 1H), 4.01 (dd, 1H). ¹⁹F NMR (CDC₃) δ−64.7 (s, 3F), −80.3 (s, 3F), −111.0 (m, 1F). HRMS calcd. for C₁₇H₁₂F₇NO₂: 396.0854 [M+H]⁺, found: 396.0821.

EXAMPLE 664

2,2,2-trifluoro-1-[[[(3-fluorophenyl)[3-(trifluoromethyl)phenyl]-methyl]amino]methyl]ethyl Acetate

A solution of 3-[(3-fluorophenyl)[[3-(3-trifluoromethyl)phenyl]methyl]amino]-1,1,1-tri-fluoro-2-propanol (200 mg, 0.52 mmol) from EX-1 in triethylamine (0.6 mL) and acetic anhydride (0.5 mL) was stirred and heated to 80° C. for 1 h. The mixture was cooled and diluted with water (20 mL) and extracted into ether (2×40 mL), which was washed with 0.1 N NaOH and water. The ether solution was dried over anhydrous MgSO₄. The ether was removed in vacuo giving the desired 2,2,2-trifluoro-1-[[[(3-fluorophenyl)[3-(trifluoromethyl)phenyl]methyl]amino]methyl]ethyl acetate product as an amber oil, 98% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.42-7.59 (m, 3H), 7.38 (d 1H), 7.18 (q, 1H), 6.42-6.56 (m, 3H), 5.69 (m, 1H), 4.64 (ABq, 2H), 3.89 (d, 1H), 3.87(s, 1H), 1.98 (s, 3H). ¹⁹F NMR (CDCl₃) δ64.0 (s, 3F), −77.2 (s, 3F), −1 12.9 (s, 1F). HRMS calcd. for C₁₉H₁₆F₇NO₂: 424.1148 [M+H]⁺, found: 424.1159.

EXAMPLE 665

1,1′-[methylenebis[3,1-phenylene[[[3-(trifluoromethoxy)phenyl]methyl]imino]]]bis[3,3,3-trifluoro-2-propanol]

EX-665A) A solution of 3,3′-diaminophenylmethane (1.48 g, 7.5 mmol) and 3-trifluoromethoxy-benzaldehyde (2.85 g, 15 mmol) in cyclohexane (50 mL) was heated under reflux for 5 h using a Dean-Stark trap to remove water. The solvent was removed in vacuo, and the residue was dissolved in methanol (30 mL). The solution was stirred and cooled to 0° C., and solid sodium borohydride was added (0.87 g, 23 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h, then acidified with 1 N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with diethyl ether (3×30 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO₄, and evaporated to give 3.19 g (78%) of the desired 3,3′-N,N′-bis(trifluoromethoxyphenyl)diamino-phenylmethane product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=546 [M⁺].

The amine (2.18 g, 4 mmol) product from EX-665A and 1,1,1-trifluoro-2,3-epoxy-propane (0.67 g, 6 mmol) were combined in a sealed vial and heated to 95° C. for 2 days, at which time HPLC analysis indicated that little secondary amine starting material remained. The excess oxirane was removed under nitrogen, and the crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:12) to give 2.0 g (67%) of the desired 1,1′-[methylenebis[3,1-phenylene[[[3-(trifluoromethoxy)phenyl]methyl]imino]]]bis-[3,3,3-trifluoro-2-propanol] product as a light amber oil, 99% pure by HPLC analysis. ¹H NMR (CDCl₃) δ7.30 (t, 2H), 7.10 (m, 6H), 7.02 (s, 2H), 6.58 (m, 4H), 6.52 (s, 2H), 4.60 (s, 4H), 4.22 (m, 2H), 3.80 (s, 2H), 3.79 (dd, 2H), 3.48 (dd, 2H), 2.60 (br s, 2H). ¹⁹F NMR (CDCl₃) δ−66.2 (s, 6F), −79.2 (d, 6F). HRMS calcd. for C₃₅H₃₀F₁₂N₂O₄: 771.2092 [M+H]⁺, found: 771.2072.

EXAMPLE EX-666

4-[[(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-butanol

EX-666A) The 4-amino-2-hydroxy-1,1,1-trifluorobutane (1.0 g, 7.0 mmol) from EX-611A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.5 g, 7.0 mmol) were dissolved in 20 mL of dichloroethane and acetic acid (0.40 mL, 7.7 mmol), then solid NaBH(OAc)₃ (1.8 g, 8.4 mmol) was added. The mixture was stirred at room temperature for 3 d, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄, and evaporated to give 1.6 g of crude product, which was purified by reverse phase HPLC to give 0.90 g (37%) of the desired 4-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-butanol product as a yellow oil. HRMS calcd. for C₁₃H₁₄F₇NO₂: 350.0991 [M+H]⁺, found: 350.0971.

The 1,1,1-trifluoro[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-2-butanol (0.35 g, 1 mmol) from EX-666A, 3-(4-fluorophenoxy)bromobenzene (0.32 g, 1.2 mmol), Pd₂(dba)₂ (18 mg, 0.02 mmol), (R,+) BINAP (49 mg, 0.08 mmol), and Cs₂CO₃ (0.46 g, 1.4 mmol) were mixed in 9 mL of toluene and heated to 100° C. for over 2 weeks, at which time FABMS (m/z=536.3 [M+H]⁺) indicated that the desired 4-[[(4-fluorophenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-tri-fluoro-2-butanol product had formed.

Based on the preceding procedures, other substituted 3-[(N-aryl)-[[aryl]methyl]amino]-halo-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Tables 43, 46, and 47. Substituted 3-[(N-aralkyl)-[[aralkyl]amino]-halo-2-propanols can also be prepared by one skilled in the art using similar methods, as shown in Example Tables 44 and 45. Substituted 3-[(N-aryl)-[[aryl]methyl]amino]-haloalkoxy-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 48.

Example Table 43. 3-[(N-aryl)-[(aryl)methyl]amino]- 1,1,1-trifluoro-2-propanols

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H]⁺ [M + H]⁺ 667 2-OCH₃ 4-CH₃ 340.1524 340.1492 668 2-OCH₃ 3-CH₃ 340.1524 340.1527 669 2-OCH₃ 3-CF₃ 394.1242 394.1239 670 3-F 2-CF₃ 382.1042 382.1029 671 3-F 2-CH₃ 328.1325 328.1319 672 4-CF₃ 4-CH₃ 378.1293 378.1273 673 2-CF₃ 4-CH₃ 378.1293 378.1284 674 3-F 3-(3-CF₃-phenoxy) 474.1304 474.1276 675 3-F 3-(4-OCH₃- 436.1536 436.1532 phenoxy) 676 3-F 3-(4-Cl-phenoxy) 440.1040 440.1048 677 3-F 3,5-(CF₃)₂ 450.0916 450.0923 678 2,3-difluoro 3-CH₃ 346.1230 346.1209 679 2-F, 3-CF₃ 4-CH₃ 396.1198 396.1200 680 2-F, 3-CF₃ 3-CH₃ 396.1198 396.1180 681 2,3-difluoro 4-CH₃ 346.1230 346.1228 682 2-OCH₃ 4-CF₃ 394.1242 394.1246 683 3-OCF₃ 4-benzyloxy 486.1504 486.1538 684 3-phenoxy 2-NO₂, 4-Cl 467.9 467.9 685 3-phenoxy 4-(3,4-Cl₂- 548 548 phenoxy) 686 3-phenoxy 4-OCH₃ 418 418 687 3-phenoxy 3,4-(OCF₂CF₂O) 518.1202 518.1286 688 3-OCF₃ 3-CF₃ 448 448 689 4-phenyl 3-CF₃ 440.1449 440.1430 690 3,5-(CF₃)₂ 3-phenoxy 524 524 691 2,5-(CF₃)₂ 3-CF₃ 500 500 692 3-OH 3-OCF₃ 396.1034 396.1053 693 3-[4-(propan- 3-OCF₂CF₂H 560.1672 560.1694 oyl)phenoxyl

Example Table 44. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]- 1,1,1-trifluoro-2-propanols

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H] 694 3-Cl 3-OCF₃ 428.0852 428.0817 695 3-Br 3-OCH₃ 472.0347 472.0312 696 2-F 2-CF₃ 396.1198 396.1193

Example Table 45. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]- 1,1,1-trifluoro-2-propanols

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H] 697 3-OCF₃ 3-OCF₃ 442.1253 442.1232

Example Table 46. 3-[N-(aryl)-N-(aralkyl)amino]- 1,1,1-trifluoro-2-propanols

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H] [M + H] 698 3-OCF₃- 2-methoxy- 500.1297 500.1295 benzyl dibenzofuran-3-yl 699 3-OCF₃- 2-fluorenyl 468.1398 468.1374 benzyl

Example Table 47. 3-[N-(aryl)-[(aryl)methyl]amino]- 1,1,1-trifluoro-2-propanols

Calculated Observed Ex. Mass Mass No. R_(SUB1)—N—R_(SUB2) [M + H] [M + H] 700

280.0949 280.0938

Example Table 48. 3-[N-(aryl)-N-(aralkyl)amino]- 1-haloalkoxy-2-propanols

Calculated Observed Ex. Mass Mass No. R_(SUB1) [M + H] [M + H] 701 F 584.1483 584.1473 702 CF₃ 634.1451 634.1432

Based on the preceding procedures, additional substituted 3-[(N-aryl)-[[aryl]methyl]amino]-halo-2-propanols are prepared by one skilled in the art using similar methods, as shown in the multiple sections of Example Table 49. Substituted 4-[N-(aryl)-[(aryl)methyl]amino]-1,1,2,2-pentafluoro-3-butanols are prepared by one skilled in the art using similar methods, as shown in Example Table 50. Substituted 3-[N-(aryl)-[(aryl)oxy]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 51. Substituted 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-butanols are prepared by one skilled in the art using similar methods, as shown in Example Table 52.

Substituted 3-[N,N′-(diaryl)amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 53. Substituted 2-[N-(aryl)-[(aryl)methyl]amino]-1-trifluoromethylcyclopentanols are prepared by one skilled in the art using similar methods, as shown in Example Table 54.

Example Table 49. Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1,1,1-trifluoro-2-propanols. Ex. No. R_(SUB1)

703 3-isopropyl 704 2-Cl, 3-Cl 705 3-CF₃O 706 4-F 707 4-CH₃ 708 2-F, 5-Br 709 3-CHF₂O 710 3-CH₃CH₂ 711 3-CH₃, 5-CH₃ 712 3-(CH₃)₃C 713 4-F, 3-CH₃ 714 3-Cl, 4-Cl 715 3,4-(CH₂)₄ 716 3-HCF₂CF₂O 717 H 718 3-(CH₃)₂N 719 3-cyclopropyl 720 3-(2-furyl) 721 3-CF₃CF₂ 722 4-NH₂ 723 3-CH₃, 4-CH₃, 5-CH₃ 724 4-CH₃CH₂CH₂O 725 2-NO₂

726 3-isopropyl 727 2-Cl, 3-Cl 728 3-CF₃O 729 4-F 730 4-CH₃ 731 2-F, 5-Br 732 2-Br, 5-F 733 3-CH₃CH₂ 734 3-CH₃, 5-CH₃ 735 3-(CH₃)₃C 736 4-F, 3-CH₃ 737 3-Cl, 4-Cl 738 3,4-(CH₂)₄ 739 3-HCF₂CF₂O 740 3-CHF₂O 741 3-(CH₃)₂N 742 3-cyclopropyl 743 3-(2-furyl) 744 3-CF₃CF₂ 745 4-NH₂ 746 3-CH₃, 4-CH₃, 5-CH₃ 747 4-CH₃CH₂CH₂O 748 2-NO₂

749 3-isopropyl 750 2-Cl, 3-Cl 751 3-CF₃O 752 4-F 753 4-CH₃ 754 2-F, 5-Br 755 4-Cl, 3-CH₃CH₂ 756 3-CH₃CH₂ 757 3-CH₃, 5-CH₃ 758 3-(CH₃)₃C 759 4-F, 3-CH₃ 760 3-Cl, 4-Cl 761 3,4-(CH₂)₄ 762 3-HCF₂CF₂O 763 3-CHF₂O 764 3-(CH₃)₂N 765 3-cyclopropyl 766 3-(2-furyl) 767 3-CF₃CF₂ 768 4-NH₂ 769 3-CH₃, 4-CH₃, 5-CH₃ 770 4-CH₃CH₂CH₂O 771 2-NO₂

772 3-isopropyl 773 2-Cl, 3-Cl 774 3-CF₃O 775 4-F 776 4-CH₃ 777 2-F,5-Br 778 4-Cl, 3-CH₃CH₂ 779 3-CH₃CH₂ 780 3-CH₃, 5-CH₃ 781 3-(CH₃)₃C 782 4-F, 3-CH₃ 783 3-Cl, 4-Cl 784 3,4-(CH₂)₄ 785 3-HCF₂CF₂O 786 3-CHF₂O 787 3-(CH₃)₂N 788 3-cyclopropyl 789 3-(2-furyl) 790 3-CF₃CF₂ 791 4-NH₂ 792 3-CH₃, 4-CH₃, 5-CH₃ 793 4-CH₃CH₂CH₂O 794 2-NO₂

795 3-isopropyl 796 2-Cl, 3-Cl 797 3-CF₃O 798 4-F 799 4-CH₃ 800 2-F, 5-Br 801 4-Cl, 3-CH₃CH₂ 802 3-CH₃CH₂ 803 3-CH₃, 5-CH₃ 804 3-(CH₃)₃C 805 4-F, 3-CH₃ 806 3-Cl, 4-Cl 807 3,4-(CH₂)₄ 808 3-HCF₂CF₂O 809 3-CHF₂O 810 3-(CH₃)₂N 811 3-cyclopropyl 812 3-(2-furyl) 813 3-CF₃CF₂ 814 4-NH₂ 815 3-CH₃, 4-CH₃, 5-CH₃ 816 4-CH₃CH₂CH₂O 817 2-NO₂

818 3-isopropyl 819 2-Cl, 3-Cl 820 3-CF₃O 821 4-F 822 4-CH₃ 823 2-F, 5-Br 824 4-Cl, 3-CH₃CH₂ 825 3-CH₃CH₂ 826 3-CH₃, 5-CH₃ 827 3-(CH₃)₃C 828 4-F, 3-CH₃ 829 3-Cl, 4-Cl 830 3,4-(CH₂)₄ 831 3-HCF₂CF₂O 832 3-CHF₂O 833 3-(CH₃)₂N 834 3-cyclopropyl 835 3-(2-furyl) 836 3-CF₃CF₂ 837 4-NH₂ 838 3-CH₃, 4-CH₃, 5-CH₃ 839 4-CH₃CH₂CH₂O 840 2-NO₂

841 3-isopropyl 842 2-Cl, 3-Cl 843 3-CF₃O 844 4-F 845 4-CH₃ 846 2-F, 5-Br 847 4-Cl, 3-CH₃CH₂ 848 3-CH₃CH₂ 849 3-CH₃, 5-CH₃ 850 3-(CH₃)₃C 851 4-F, 3-CH₃ 852 3-Cl, 4-Cl 853 3,4-(CH₂)₄ 854 3-HCF₂CF₂O 855 3-CHF₂O 856 3-(CH₃)₂N 857 3-cyclopropyl 858 3-(2-furyl) 859 3-CF₃CF₂ 860 4-NH₂ 861 3-CH₃, 4-CH₃, 5-CH₃ 862 4-CH₃CH₂CH₂O 863 2-NO₂

864 3-isopropyl 865 2-Cl,3-Cl 866 3-CF₃O 867 4-F 868 4-CH₃ 869 2-F, 5-Br 870 4-Cl, 3-CH₃CH₂ 871 3-CH₃CH₂ 872 3-CH₃, 5-CH₃ 873 3-(CH₃)₃C 874 4-F, 3-CH₃ 875 3-Cl, 4-Cl 876 3,4-(CH₂)₄ 877 3-HCF₂CF₂O 878 3-CHF₂O 879 3-(CH₃)₂N 880 3-cyclopropyl 881 3-(2-furyl) 882 3-CF₃CF₂ 883 4-NH₂ 884 3-CH₃, 4-CH₃, 5-CH₃ 885 4-CH₃CH₂CH₂O 886 2-NO₂

887 3-isopropyl 888 2-Cl, 3-Cl 889 3-CF₃O 890 4-F 891 4-CH₃ 892 2-F, 5-Br 893 4-Cl, 3-CH₃CH₂ 894 3-CH₃CH₂ 895 3-CH₃, 5-CH₃ 896 3-(CH₃)₃C 897 4-F, 3-CH₃ 898 3-Cl, 4-Cl 899 3,4-(CH₂)₄ 900 3-HCF₂CF₂O 901 3-CHF₂O 902 3-(CH₃)₂N 903 3-cyclopropyl 904 3-(2-furyl) 905 3-CF₃CF₂ 906 4-NH₂ 907 3-CH₃, 4-CH₃, 5-CH₃ 908 4-CH₃CH₂CH₂O 909 2-NO₂

910 3-isopropyl 911 2-Cl, 3-Cl 912 3-CF₃O 913 4-F 914 4-CH₃ 915 2-F, 5-Br 916 4-Cl, 3-CH₃CH₂ 917 3-CH₃CH₂ 918 3-CH₃, 5-CH₃ 919 3-(CH₃)₃C 920 4-F, 3-CH₃ 921 3-Cl, 4-Cl 922 3,4-(CH₂)₄ 923 3-HCF₂CF₂O 924 3-CHF₂O 925 3-(CH₃)₂N 926 3-cyclopropyl 927 3-(2-furyl) 928 3-CF₃CF₂ 929 4-NH₂ 930 3-CH₃, 4-CH₃, 5-CH₃ 931 4-CH₃CH₂CH₂O 932 2-NO₂

933 3-isopropyl 934 2-Cl, 3-Cl 935 3-CF₃O 936 4-F 937 4-CH₃ 938 2-F, 5-Br 939 4-Cl, 3-CH₃CH₂ 940 3-CH₃CH₂ 941 3-CH₃, 5-CH₃ 942 3-(CH₃)₃C 943 4-F, 3-CH₃ 944 3-Cl, 4-Cl 945 3,4-(CH₂)₄ 946 3-HCF₂CF₂O 947 3-CHF₂O 948 3-(CH₃)₂N 949 3-cyclopropyl 950 3-(2-furyl) 951 3-CF₃CF₂ 952 4-NH₂ 953 3-CH₃, 4-CH₃, 5-CH₃ 954 4-CH₃CH₂CH₂O 955 2-NO₂

956 3-isopropyl 957 2-Cl, 3-Cl 958 3-CF₃O 959 4-F 960 4-CH₃ 961 2-F, 5-Br 962 2-Br, 5-F 963 3-CH₃CH₂ 964 3-CH₃, 5-CH₃ 965 3-(CH₃)₃C 966 4-F, 3-CH₃ 967 3-Cl, 4-Cl 968 3,4-(CH₂)₄ 969 3-HCF₂CF₂O 970 3-CHF₂O 971 3-(CH₃)₂N 972 3-cyclopropyl 973 3-(2-furyl) 974 3-CF₃CF₂ 975 4-NH₂ 976 3-CH₃, 4-CH₃, 5-CH₃ 977 4-CH₃CH₂CH₂O 978 2-NO₂

979 3-isopropyl 980 2-Cl, 3-Cl 981 3-CF₃O 982 4-F 983 4-CH₃ 984 2-F, 5-Br 985 4-Cl, 3-CH₃CH₂ 986 3-CH₃CH₂ 987 3-CH₃, 5-CH₃ 988 3-(CH₃)₃C 989 4-F, 3-CH₃ 990 3-Cl, 4-Cl 991 3,4-(CH₂)₄ 992 3-HCF₂CF₂O 993 3-CHF₂O 994 3-(CH₃)₂N 995 3-cyclopropyl 996 3-(2-furyl) 997 3-CF₃CF₂ 998 4-NH₂ 999 3-CH₃, 4-CH₃, 5-CH₃ 1000 4-CH₃CH₂CH₂O 1001 2-NO₂

1002 3-isopropyl 1003 2-Cl, 3-Cl 1004 3-CF₃O 1005 4-F 1006 4-CH₃ 1007 2-F, 5-Br 1008 4-Cl, 3-CH₃CH₂ 1009 3-CH₃CH₂ 1010 3-CH₃, 5-CH₃ 1011 3-(CH₃)₃C 1012 4-F, 3-CH₃ 1013 3-Cl, 4-Cl 1014 3,4-(CH₂)₄ 1015 3-HCF₂CF₂O 1016 3-CHF₂O 1017 3-(CH₃)₂N 1018 3-cyclopropyl 1019 3-(2-furyl) 1020 3-CF₃CF₂ 1021 4-NH₂ 1022 3-CH₃, 4-CH₃, 5-CH₃ 1023 4-CH₃CH₂CH₂O 1024 2-NO₂

1025 3-isopropyl 1026 2-Cl, 3-Cl 1027 3-CF₃O 1028 4-F 1029 4-CH₃ 1030 2-F, 5-Br 1031 4-Cl, 3-CH₃CH₂ 1032 3-CH₃CH₂ 1033 3-CH₃, 5-CH₃ 1034 3-(CH₃)₃C 1035 4-F, 3-CH₃ 1036 3-Cl, 4-Cl 1037 3,4-(CH₂)₄ 1038 3-HCF₂CF₂O 1039 3-CHF₂O 1040 3-(CH₃)₂N 1041 3-cyclopropyl 1042 3-(2-furyl) 1043 3-CF₃CF₂ 1044 4-NH₂ 1045 3-CH₃, 4-CH₃, 5-CH₃ 1046 4-CH₃CH₂CH₂O 1047 2-NO₂ R_(SUB2)

1048 3-CF₃O-benzyloxy 1049 3-CF₃-benzyloxy 1050 3-F, 5-F-benzyloxy 1051 cyclohexylmethyleneoxy 1052 benzyloxy 1053 3-CF₃, 5-CF₃-benzyloxy 1054 4-CF₃O-benzyloxy 1055 4-CH₃CH₂-benzyloxy 1056 isopropoxy 1057 3-CF₃-benzyl 1058 isopropylthio 1059 cyclopentoxy 1060 3-Cl-5-pyridinyloxy 1061 3-CF₃S-benzyloxy 1062 3-CH₃, 4-CH₃-benzyloxy 1063 2-F, 3-CF₃-benzyloxy 1064 3-F, 5-CF₃-benzyloxy 1065 4-(CH₃)₂CH-benzyloxy 1066 1-phenylethoxy 1067 4-F, 3-CH₃-benzoyl 1068 3-CF₃-phenyl- 1069 4-CH₃O-phenylamino- 1070 4-NO₂-phenylthio-

1071 3-CF₃O-benzyloxy 1072 3-CF₃-benzyloxy 1073 3-F, 5-F-benzyloxy 1074 cyclohexylmethyleneoxy 1075 benzyloxy 1076 3-CF₃, 5-CF₃-benzyloxy 1077 4-CF₃O-benzyloxy 1078 4-CH₃CH₂-benzyloxy 1079 isopropoxy 1080 3-CF₃-benzyl 1081 isopropylthio 1082 cyclopentoxy 1083 3-Cl-5-pyridinyloxy 1084 3-CF₃S-benzyloxy 1085 3-CH₃, 4-CH₃-benzyloxy 1086 2-F, 3-CF₃-benzyloxy 1087 3-F, 5-CF₃-benzyloxy 1088 4-(CH₃)₂CH-benzyloxy 1089 1-phenylethoxy 1090 4-F, 3-CH₃-benzoyl 1091 3-CF₃-phenyl- 1092 4-CH₃O-phenylamino- 1093 4-NO₂-phenylthio-

1094 3-CF₃O-benzyloxy 1095 3-CF₃-benzyloxy 1096 3-F, 5-F-benzyloxy 1097 cyclohexylmethyleneoxy 1098 benzyloxy 1099 3-CF₃, 5-CF₃-benzyloxy 1100 4-CF₃O-benzyloxy 1101 4-CH₃CH₂-benzyloxy 1102 isopropoxy 1103 3-CF₃-benzyl 1104 isopropylthio 1105 cyclopentoxy 1106 3-Cl-5-pyridinyloxy 1107 3-CF₃S-benzyloxy 1108 3-CH₃, 4-CH₃-benzyloxy 1109 2-F, 3-CF₃-benzyloxy 1110 3-F, 5-CF₃-benzyloxy 1111 4-(CH₃)₂CH-benzyloxy 1112 1-phenylethoxy 1113 4-F, 3-CH₃-benzoyl 1114 3-CF₃-phenyl- 1115 4-CH₃O-phenylamino- 1116 4-NO₂-phenylthio-

1117 3-CF₃O-benzyloxy 1118 3-CF₃-benzyloxy 1119 3-F, 5-F-benzyloxy 1120 cyclohexylmethyleneoxy 1121 benzyloxy 1122 3-CF₃, 5-CF₃-benzyloxy 1123 4-CF₃O-benzyloxy 1124 4-CH₃CH₂-benzyloxy 1125 isopropoxy 1126 3-CF₃-benzyl 1127 isopropylthio 1128 cyclopentoxy 1129 3-Cl-5-pyridinyloxy 1130 3-CF₃S-benzyloxy 1131 3-CH₃, 4-CH₃-benzyloxy 1132 2-F, 3-CF₃-benzyloxy 1133 3-F, 5-CF₃-benzyloxy 1134 4-(CH₃)₂CH-benzyloxy 1135 1-phenylethoxy 1136 4-F, 3-CH₃-benzoyl 1137 3-CF₃-phenyl- 1138 4-CH₃O-phenylamino- 1139 4-NO₂-phenylthio-

1140 3-CF₃O-benzyloxy 1141 3-CF₃-benzyloxy 1142 3-F, 5-F-benzyloxy 1143 cyclohexylmethyleneoxy 1144 benzyloxy 1145 3-CF₃, 5-CF₃-benzyloxy 1146 4-CF₃O-benzyloxy 1147 4-CH₃CH₂-benzyloxy 1148 isopropoxy 1149 3-CF₃-benzyl 1150 isopropylthio 1151 cyclopentoxy 1152 3-Cl-5-pyridinyloxy 1153 3-CF₃S-benzyloxy 1154 3-CH₃, 4-CH₃-benzyloxy 1155 2-F, 3-CF₃-benzyloxy 1156 3-F, 5-CF₃-benzyloxy 1157 4-(CH₃)₂CH-benzyloxy 1158 1-phenylethoxy 1159 4-F, 3-CH₃-benzoyl 1160 3-CF₃-phenyl- 1161 4-CH₃O-phenylamino- 1162 4-NO₂-phenylthio-

1163 3-CF₃O-benzyloxy 1164 3-CF₃-benzyloxy 1165 3-F, 5-F-benzyloxy 1166 cyclohexylmethyleneoxy 1167 benzyloxy 1168 3-CF₃, 5-CF₃-benzyloxy 1169 4-CF₃O-benzyloxy 1170 4-CH₃CH₂-benzyloxy 1171 isopropoxy 1172 3-CF₃-benzyl 1173 isopropylthio 1174 cyclopentoxy 1175 3-Cl-5-pyridinyloxy 1176 3-CF₃S-benzyloxy 1177 3-CH₃, 4-CH₃-benzyloxy 1178 2-F, 3-CF₃-benzyloxy 1179 3-F, 5-CF₃-benzyloxy 1180 4-(CH₃)₂CH-benzyloxy 1181 1-phenylethoxy 1182 4-F, 3-CH₃-benzoyl 1183 3-CF₃-phenyl- 1184 4-CH₃O-phenylamino- 1185 4-NO₂-phenylthio-

1186 3-CF₃O-benzyloxy 1187 3-CF₃-benzyloxy 1188 3-F, 5-F-benzyloxy 1189 cyclohexylmethyleneoxy 1190 benzyloxy 1191 3-CF₃, 5-CF₃-benzyloxy 1192 4-CF₃O-benzyloxy 1193 4-CH₃CH₂-benzyloxy 1194 isopropoxy 1195 3-CF₃-benzyl 1196 isopropylthio 1197 cyclopentoxy 1198 3-Cl-5-pyridinyloxy 1199 3-CF₃S-benzyloxy 1200 3-CH₃, 4-CH₃-benzyloxy 1201 2-F, 3-CF₃-benzyloxy 1202 3-F, 5-CF₃-benzyloxy 1203 4-(CH₃)₂CH-benzyloxy 1204 1-phenylethoxy 1205 4-F, 3-CH₃-benzoyl 1206 3-CF₃-phenyl- 1207 4-CH₃O-phenylamino- 1208 4-NO₂-phenylthio-

1209 3-CF₃O-benzyloxy 1210 3-CF₃-benzyloxy 1211 3-F, 5-F-benzyloxy 1212 cyclohexylmethyleneoxy 1213 benzyloxy 1214 3-CF₃, 5-CF₃-benzyloxy 1215 4-CF₃O-benzyloxy 1216 4-CH₃CH₂-benzyloxy 1217 isopropoxy 1218 3-CF₃-benzyl 1219 isopropylthio 1220 cyclopentoxy 1221 3-Cl-5-pyridinyloxy 1222 3-CF₃S-benzyloxy 1223 3-CH₃, 4-CH₃-benzyloxy 1224 2-F, 3-CF₃-benzyloxy 1225 3-F, 5-CF₃-benzyloxy 1226 4-(CH₃)₂CH-benzyloxy 1227 1-phenylethoxy 1228 4-F, 3-CH₃-benzoyl 1229 3-CF₃-phenyl- 1230 4-CH₃O-phenylamino- 1231 4-NO₂-phenylthio-

1232 3-CF₃O-benzyloxy 1233 3-CF₃-benzyloxy 1234 3-F, 5-F-benzyloxy 1235 cyclohexylmethyleneoxy 1236 benzyloxy 1237 3-CF₃, 5-CF₃-benzyloxy 1238 4-CF₃O-benzyloxy 1239 4-CH₃CH₂-benzyloxy 1240 isopropoxy 1241 3-CF₃-benzyl 1242 isopropylthio 1243 cyclopentoxy 1244 3-Cl-5-pyridinyloxy 1245 3-CF₃S-benzyloxy 1246 3-CH₃, 4-CH₃-benzyloxy 1247 2-F, 3-CF₃-benzyloxy 1248 3-F, 5-CF₃-benzyloxy 1249 4-(CH₃)₂CH-benzyloxy 1250 1-phenylethoxy 1251 4-F, 3-CH₃-benzoyl 1252 3-CF₃-phenyl- 1253 4-CH₃O-phenylamino- 1254 4-NO₂-phenylthio-

1255 3-CF₃O-benzyloxy 1256 3-CF₃-benzyloxy 1257 3-F, 5-F-benzyloxy 1258 cyclohexylmethyleneoxy 1259 benzyloxy 1260 3-CF₃, 5-CF₃-benzyloxy 1261 4-CF₃O-benzyloxy 1262 4-CH₃CH₂-benzyloxy 1263 isopropoxy 1264 3-CF₃-benzyl 1265 isopropylthio 1266 cyclopentoxy 1267 3-Cl-5-pyridinyloxy 1268 3-CF₃S-benzyloxy 1269 3-CH₃, 4-CH₃-benzyloxy 1270 2-F, 3-CF₃-benzyloxy 1271 3-F, 5-CF₃-benzyloxy 1272 4-(CH₃)₂CH-benzyloxy 1273 1-phenylethoxy 1274 4-F, 3-CH₃-benzoyl 1275 3-CF₃-phenyl- 1276 4-CH₃O-phenylamino- 1277 4-NO₂-phenylthio-

1278 3-CF₃O-benzyloxy 1279 3-CF₃-benzyloxy 1280 3-F, 5-F-benzyloxy 1281 cyclohexylmethyleneoxy 1282 benzyloxy 1283 3-CF₃, 5-CF₃-benzyloxy 1284 4-CF₃O-benzyloxy 1285 4-CH₃CH₂-benzyloxy 1286 isopropoxy 1287 3-CF₃-benzyl 1288 isopropylthio 1289 cyclopentoxy 1290 3-Cl-5-pyridinyloxy 1291 3-CF₃S-benzyloxy 1292 3-CH₃, 4-CH₃-benzyloxy 1293 2-F, 3-CF₃-benzyloxy 1294 3-F, 5-CF₃-benzyloxy 1295 4-(CH₃)₂CH-benzyloxy 1296 1-phenylethoxy 1297 4-F, 3-CH₃-benzoyl 1298 3-CF₃-phenyl- 1299 4-CH₃O-phenylamino- 1300 4-NO₂-phenylthio-

1301 3-CF₃O-benzyloxy 1302 3-CF₃-benzyloxy 1303 3-F, 5-F-benzyloxy 1304 cyclohexylmethyleneoxy 1305 benzyloxy 1306 3-CF₃, 5-CF₃-benzyloxy 1307 4-CF₃O-benzyloxy 1308 4-CH₃CH₂-benzyloxy 1309 isopropoxy 1310 3-CF₃-benzyl 1311 isopropylthio 1312 cyclopentoxy 1313 3-Cl-5-pyridinyloxy 1314 3-CF₃S-benzyloxy 1315 3-CH₃, 4-CH₃-benzyloxy 1316 2-F, 3-CF₃-benzyloxy 1317 3-F, 5-CF₃-benzyloxy 1318 4-(CH₃)₂CH-benzyloxy 1319 1-phenylethoxy 1320 4-F, 3-CH₃-benzoyl 1321 3-CF₃-phenyl- 1322 4-CH₃O-phenylamino- 1323 4-NO₂-phenylthio-

1324 3-CF₃O-benzyloxy 1325 3-CF₃-benzyloxy 1326 3-F, 5-F-benzyloxy 1327 cyclohexylmethyleneoxy 1328 benzyloxy 1329 3-CF₃, 5-CF₃-benzyloxy 1330 4-CF₃O-benzyloxy 1331 4-CH₃CH₂-benzyloxy 1332 isopropoxy 1333 3-CF₃-benzyl 1334 isopropylthio 1335 cyclopentoxy 1336 3-Cl-5-pyridinyloxy 1337 3-CF₃S-benzyloxy 1338 3-CH₃, 4-CH₃-benzyloxy 1339 2-F, 3-CF₃-benzyloxy 1340 3-F, 5-CF₃-benzyloxy 1341 4-(CH₃)₂CH-benzyloxy 1342 1-phenylethoxy 1343 4-F, 3-CH₃-benzoyl 1344 3-CF₃-phenyl- 1345 4-CH₃O-phenylamino- 1346 4-NO₂-phenylthio-

1347 3-CF₃O-benzyloxy 1348 3-CF₃-benzyloxy 1349 3-F, 5-F-benzyloxy 1350 cyclohexylmethyleneoxy 1351 benzyloxy 1352 3-CF₃, 5-CF₃-benzyloxy 1353 4-CF₃O-benzyloxy 1354 4-CH₃CH₂-benzyloxy 1355 isopropoxy 1356 3-CF₃-benzyl 1357 isopropylthio 1358 cyclopentoxy 1359 3-Cl-5-pyridinyloxy 1360 3-CF₃S-benzyloxy 1361 3-CH₃, 4-CH₃-benzyloxy 1362 2-F, 3-CF₃-benzyloxy 1363 3-F, 5-CF₃-benzyloxy 1364 4-(CH₃)₂CH-benzyloxy 1365 1-phenylethoxy 1366 4-F, 3-CH₃-benzoyl 1367 3-CF₃-phenyl- 1368 4-CH₃O-phenylamino- 1369 4-NO₂-phenylthio-

1370 3-CF₃O-benzyloxy 1371 3-CF₃-benzyloxy 1372 3-F, 5-F-benzyloxy 1373 cyclohexylmethyleneoxy 1374 benzyloxy 1375 3-CF₃, 5-CF₃-benzyloxy 1376 4-CF₃O-benzyloxy 1377 4-CH₃CH₂-benzyloxy 1378 isopropoxy 1379 3-CF₃-benzyl 1380 isopropylthio 1381 cyclopentoxy 1382 3-Cl-5-pyridinyloxy 1383 3-CF₃S-benzyloxy 1384 3-CH₃, 4-CH₃-benzyloxy 1385 2-F, 3-CF₃-benzyloxy 1386 3-F, 5-CF₃-benzyloxy 1387 4-(CH₃)₂CH-benzyloxy 1388 1-phenylethoxy 1389 4-F, 3-CH₃-benzoyl 1390 3-CF₃-phenyl- 1391 4-CH₃O-phenylamino- 1392 4-NO₂-phenylthio-

Example Table 50. Substituted 4-[N-(aryl)-[(aryl)methyl]amino]- 1,1,1,2,2-pentafluoro-3-butanols

Ex. No. R_(SUB1) 1393 3-isopropyl 1394 2-Cl, 3-Cl 1395 3-CF₃O 1396 4-F 1397 4-CH₃ 1398 2-F, 5-Br 1399 4-Cl, 3-CH₃CH₂ 1400 3-CH₃CH₂ 1401 3-CH₃, 5-CH₃ 1402 3-(CH₃)₃C 1403 4-F, 3-CH₃ 1404 3-Cl, 4-Cl 1405 3,4-(CH₂)₄ 1406 3-HCF₂CF₂O 1407 3-CHF₂O 1408 3-(CH₃)₂N 1409 3-cyclopropyl 1410 3-(2-furyl) 1411 3-CF₃CF₂ 1412 4-NH₂ 1413 3-CH₃, 4-CH₃, 5-CH₃ 1414 4-CH₃CH₂CH₂O 1415 2-NO₂

Ex. No. R_(SUB2) 1416 3-CF₃O-benzyloxy 1417 3-CF₃-benzyloxy 1418 3-F, 5-F-benzyloxy 1419 cyclohexylmethyleneoxy 1420 benzyloxy 1421 3-CF₃, 5-CF₃-benzyloxy 1422 4-CF₃O-benzyloxy 1423 4-CH₃CH₂-benzyloxy 1424 isopropoxy 1425 3-CF₃-benzyl 1426 isopropylthio 1427 cyclopentoxy 1428 3-Cl-5-pyridinyloxy 1429 3-CF₃S-benzyloxy 1430 3-CH₃, 4-CH₃-benzyloxy 1431 2-F, 3-CF₃-benzyloxy 1432 3-F, 5-CF₃-benzyloxy 1433 4-(CH₃)₂CH-benzyloxy 1434 1-phenylethoxy 1435 4-F, 3-CH₃-benzoyl 1436 3-CF₃-phenyl- 1437 4-CH₃O-phenylamino- 1438 4-NO₂-phenylthio-

Example Table 51. Substituted 3-[N-(aryl)-[(aryl)oxy]amino]- 1,1,1-trifluoro-2-propanols

Ex. No. R_(SUB1) 1439 3-isopropyl 1440 2-Cl, 3-Cl 1441 3-CF₃O 1442 4-F 1443 4-CH₃ 1444 2-F, 5-Br 1445 4-Cl, 3-CH₃CH₂ 1446 3-CH₃CH₂ 1447 3-CH₃, 5-CH₃ 1448 3-(CH₃)₃C 1449 4-F, 3-CH₃ 1450 3-Cl, 4-Cl 1451 3,4-(CH₂)₄ 1452 3-HCF₂CF₂O 1453 3-CHF₂O 1454 3-(CH₃)₂N 1455 3-cyclopropyl 1456 3-(2-furyl) 1457 3-CF₃CF₂ 1458 4-NH₂ 1459 3-CH₃, 4-CH₃, 5-CH₃ 1460 4-CH₃CH₂CH₂O 1461 2-NO₂

Ex. No. R_(SUB2) 1462 3-CF₃O-benzyloxy 1463 3-CF₃-benzyloxy 1464 3-F, 5-F-benzyloxy 1465 cyclohexylmethyleneoxy 1466 benzyloxy 1467 3-CF₃, 5-CF₃-benzyloxy 1468 4-CF₃O-benzyloxy 1469 4-CH₃CH₂-benzyloxy 1470 isopropoxy 1471 3-CF₃-benzyl 1472 isopropylthio 1473 cyclopentoxy 1474 3-Cl-5-pyridinyloxy 1475 3-CF₃S-benzyloxy 1476 3-CH₃, 4-CH₃-benzyloxy 1477 2-F, 3-CF₃-benzyloxy 1478 3-F, 5-CF₃-benzyloxy 1479 4-(CH₃)₂CH-benzyloxy 1480 1-phenylethoxy 1481 4-F, 3-CH₃-benzoyl 1482 3-CF₃-phenyl- 1483 4-CH₃O-phenylamino- 1484 4-NO₂-phenylthio-

Example Table 52. Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1,1,1-trifluoro-2-butanols

Ex. No. R_(SUB1) 1485 3-isopropyl 1486 2-Cl, 3-Cl 1487 3-CF₃O 1488 4-F 1489 4-CH₃ 1490 2-F, 5-Br 1491 4-Cl, 3-CH₃CH₂ 1492 3-CH₃CH₂ 1493 3-CH₃, 5-CH₃ 1494 3-(CH₃)₃C 1495 4-F, 3-CH₃ 1496 3-Cl, 4-Cl 1497 3,4-(CH₂)₄ 1498 3-HCF₂CF₂O 1499 3-CHF₂O 1500 3-(CH₃)₂N 1501 3-cyclopropyl 1502 3-(2-furyl) 1503 3-CF₃CF₂ 1504 4-NH₂ 1505 3-CH₃, 4-CH₃, 5-CH₃ 1506 4-CH₃CH₂CH₂O 1507 2-NO₂ 1508 3-isopropyl 1509 2-Cl, 3-Cl 1510 3-CF₃O 1511 4-F 1512 4-CH₃ 1513 2-F, 5-Br 1514 4-Cl, 3-CH₃CH₂ 1515 3-CH₃CH₂ 1516 3-CH₃, 5-CH₃ 1517 3-(CH₃)₃C 1518 4-F, 3-CH₃ 1519 3-Cl, 4-Cl 1520 3,4-(CH₂)₄ 1521 3-HCF₂CF₂O 1522 3-CHF₂O 1523 3-(CH₃)₂N 1524 3-cyclopropyl 1525 3-(2-furyl) 1526 3-CF₃CF₂ 1527 4-NH₂ 1528 3-CH₃, 4-CH₃, 5-CH₃ 1529 4-CH₃CH₂CH₂O 1530 2-NO₂

Ex. No. R_(SUB2) 1531 3-CF₃O-benzyloxy 1532 3-CF₃-benzyloxy 1533 3-F, 5-F-benzyloxy 1534 cyclohexylmethyleneoxy 1535 benzyloxy 1536 3-CF₃, 5-CF₃-benzyloxy 1537 4-CF₃O-benzyloxy 1538 4-CH₃CH₂-benzyloxy 1539 isopropoxy 1540 3-CF₃-benzyl 1541 isopropylthio 1542 cyclopentoxy 1543 3-Cl-5-pyridinyloxy 1544 3-CF₃S-benzyloxy 1545 3-CH₃, 4-CH₃-benzyloxy 1546 2-F, 3-CF₃-benzyloxy 1547 3-F, 5-CF₃-benzyloxy 1548 4-(CH₃)₂CH-benzyloxy 1549 1-phenylethoxy 1550 4-F, 3-CH₃-benzoyl 1551 3-CF₃-phenyl- 1552 4-CH₃O-phenylamino- 1553 4-NO₂-phenylthio- 1554 3-CF₃O-benzyloxy 1555 3-CF₃-benzyloxy 1556 3-F, 5-F-benzyloxy 1557 cyclohexylmethyleneoxy 1558 benzyloxy 1559 3-CF₃, 5-CF₃-benzyloxy 1560 4-CF₃O-benzyloxy 1561 4-CH₃CH₂-benzyloxy 1562 isopropoxy 1563 3-CF₃-benzyl 1564 isopropylthio 1565 cyclopentoxy 1566 3-Cl-5-pyridinyloxy 1567 3-CF₃S-benzyloxy 1568 3-CH₃, 4-CH₃-benzyloxy 1569 2-F, 3-CF₃-benzyloxy 1570 3-F, 5-CF₃-benzyloxy 1571 4-(CH₃)₂CH-benzyloxy 1572 1-phenylethoxy 1573 4-F, 3-CH₃-benzoyl 1574 3-CF₃-phenyl- 1575 4-CH₃O-phenylamino- 1576 4-NO₂-phenylthio-

Example Table 53. Substituted 3-[N,N′-(diaryl)amino]- 1,1,1,2,2-pentafluoro-2-propanols

Ex. No. R_(SUB1) 1577 3-isopropyl 1578 2-Cl, 3-Cl 1579 3-CF₃O 1580 4-F 1581 4-CH₃ 1582 2-F, 5-Br 1583 4-Cl, 3-CH₃CH₂ 1584 3-CH₃CH₂ 1585 3-CH₃, 5-CH₃ 1586 3-(CH₃)₃C 1587 4-F, 3-CH₃ 1588 3-Cl, 4-Cl 1589 3,4-(CH₂)₄ 1590 3-HCF₂CF₂O 1591 3-CHF₂O 1592 3-(CH₃)₂N 1593 3-cyclopropyl 1594 3-(2-furyl) 1595 3-CF₃CF₂ 1596 4-NH₂ 1597 3-CH₃, 4-CH₃, 5-CH₃ 1598 4-CH₃CH₂CH₂O 1599 2-NO₂

Ex. No. R_(SUB2) 1600 3-CF₃O-benzyloxy 1601 3-CF₃-benzyloxy 1602 3-F, 5-F-benzyloxy 1603 cyclohexylmethyleneoxy 1604 benzyloxy 1605 3-CF₃, 5-CF₃-benzyloxy 1606 4-CF₃O-benzyloxy 1607 4-CH₃CH₂-benzyloxy 1608 isopropoxy 1609 3-CF₃-benzyl 1610 isopropylthio 1611 cyclopentoxy 1612 3-Cl-5-pyridinyloxy 1613 3-CF₃S-benzyloxy 1614 3-CH₃, 4-CH₃-benzyloxy 1615 2-F, 3-CF₃-benzyloxy 1616 3-F, 5-CF₃-benzyloxy 1617 4-(CH₃)₂CH-benzyloxy 1618 1-phenylethoxy 1619 4-F, 3-CH₃-benzoyl 1620 3-CF₃-phenyl 1621 4-CH₃O-phenylamino 1622 4-NO₂-phenylthio

Example Table 54. Substituted 2-[N-(aryl)-[(aryl)methyl]amino]- 1-trifluoromethylcyclopentanols

Ex. No. R_(SUB1) 1623 3-isopropyl 1624 2-Cl, 3-Cl 1625 3-CF₃O 1626 4-F 1627 4-CH₃ 1628 2-F, 5-Br 1629 4-Cl, 3-CH₃CH₂ 1630 3-CH₃CH₂ 1631 3-CH₃, 5-CH₃ 1632 3-(CH₃)₃C 1633 4-F, 3-CH₃ 1634 3-Cl, 4-Cl 1635 3,4-(CH₂)₄ 1636 3-HCF₂CF₂O 1637 3-CHF₂O 1638 3-(CH₃)₂N 1639 3-cyclopropyl 1640 3-(2-furyl) 1641 3-CF₃CF₂ 1642 4-NH₂ 1643 3-CH₃, 4-CH₃, 5-CH₃ 1644 4-CH₃CH₂CH₂O 1645 2-NO₂

Ex. No. R_(SUB2) 1646 3-CF₃O-benzyloxy 1647 3-CF₃-benzyloxy 1648 3-F, 5-F-benzyloxy 1649 cyclohexylmethyleneoxy 1650 benzyloxy 1651 3-CF₃, 5-CF₃-benzyloxy 1652 4-CF₃O-benzyloxy 1653 4-CH₃CH₂-benzyloxy 1654 isopropoxy 1655 3-CF₃-benzyl 1656 isopropylthio 1657 cyclopentoxy 1658 3-Cl-5-pyridinyloxy 1659 3-CF₃S-benzyloxy 1660 3-CH₃, 4-CH₃-benzyloxy 1661 2-F, 3-CF₃-benzyloxy 1662 3-F, 5-CF₃-benzyloxy 1663 4-(CH₃)₂CH-benzyloxy 1664 1-phenylethoxy 1665 4-F, 3-CH₃-benzoyl 1666 3-CF₃-phenyl- 1667 4-CH₃O-phenylamino- 1668 4-NO₂-phenylthio-

EXAMPLE 1669

N-(3-phenoxyphenyl)-N-(3,3,3,2-tetrafluoropropyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine

To a solution of 3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (474 mg, 0.00094 mol) in 4.5 mL of dichloromethane at 0° C. was added (diethylamino)sulfur trifluoride (378 mg, 0.0023 mol). The reaction mixture was warmed to room temperature and stirred for 2 h, then quenched with water and extracted with dichloromethane. The organic layers were combined, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to afford 240 mg (50%) of the desired N-(3-phenoxyphenyl)-N-(3,3,3,2-tetra-fluoropropyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine product as a yellow oil. HRMS calcd. for C₂₄H₁₉F₈NO₂: 506.1366 [M+H]⁺, found: 506.1368. ¹H NMR (CDCl₃) δ7.26 (m, 3H), 7.20 (m, 5H), 6.87 (d, 2H), 6.62 (d, 1H), 6.50 (s, 1H), 6.49 (d, 1H), 5.87 (t, 1H), 4.89 (d, 1H), 4.77-4.52 (m, 1H), 4.73 (d, 1H), 4.60 (s, 2H). ¹⁹F NMR (CDCl₃) δ−69.83 (t, 3F), −88.63 (s, 2F), −137.19 (dt, 2F), −228.82 (1F).

EXAMPLE 1670

2-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-3,3,3-trifluoropropanol

To a dichloromethane (2 mL) solution of N-[(4-chloro-3-ethyl-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine (0.25 g, 0.55 mmol) and 2-diazo-3,3,3-trifluoropropionic acid p-nitrophenyl ester (0.14 g, 0.51 mmol) was added solid Rh₂(OAc)₄ (0.015 g, 0.034 mmol). The resulting green slurry was stirred at room temperature under nitrogen for 24 h. The solvent was removed to give a green oil, and the crude intermediate was dissolved in THF (4 mL). This green solution was cooled to 0° C., and a 1.0 M solution of LiAlH₄ in THF (0.6 mL, 0.6 mmol) was added dropwise. The resulting dark solution was stirred for 30 min at 0° C. and quenched by the slow addition of water. The reaction mixture was extracted with Et₂O, dried (MgSO₄) and evaporated to give a brown oil. Purification by flash column chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.032 g (11%) of the desired 2-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-3,3,3-trifluoropropanol product as a light brown oil. HRMS calcd. for C₂₆H₂₃NO₃ClF₇: 566.1333 [M+H]⁺, found: 566.1335. ¹H NMR (C₆D₆) δ0.53 (t, 1H, exchangeable with D₂O), 0.93 (t, 3H), 2.43 (t, 2H), 3.33 (m, 2H), 4.11 (s, 2H), 4.13 (m, 1H), 5.04 (tt, 1H), 6.4 (m, 3H), 6.55 (t, 1H), 6.7-6.8 (m, 5H), 6.97 (d, 1H), 7.04 (s, 1H).

EXAMPLE 1671

N-(3-phenoxyphenyl)-N-(4,4,4-trifluorobutyl)-3-(trifluoromethoxy)benzenemethanamine

EX-1671A) To a solution of 3-phenoxyaniline (10.9 g, 58.8 mmol) in 100 mL of cyclohexane was added solid NaH (60% in mineral oil, 1.96 g, 49 mmol). Then 3-trifluoromethoxybenzyl bromide (10.0 g, 39.2 mmol) was added dropwise under a nitrogen atmosphere, and the mixture was heated to reflux for 18 h, at which time TLC analysis indicated that no 3-trifluoromethoxybenzyl bromide remained. The reaction mixture was cooled to room temperature and quenched with water, then extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄, and evaporated to give crude product. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give the desired N-benzylaniline product, which contained a small portion of dibenzylated amine. This product was further purified by conversion to the corresponding HCl salt to give 11.0 g (73%) of the desired N-(3-phenoxyphenyl)-N-[(3-trifluoromethoxy)phenyl]methyl]amine hydrochloride product. HRMS calcd. for C₂₀H₁₆NO₂F₃: 360.1211 [M+H]⁺, found 360.1208.

The N-(3-phenoxyphenyl)-N-[(3-trifluoromethoxy)phenyl]methyl]amine hydrochloride (1.0 g, 2.5 mmol) product from EX-1671A was dissolved in 20 mL of THF under nitrogen. Solid NaNH₂ (50% in xylene, 0.2 g, 2.6 mmol) was added, and the mixture was stirred at room temperature. Then 1-iodo-4,4,4-trifluorobutone (1.0 g, 4.2 mmol) and additional NaNH₂ (50% in xylene, 0.2 g, 2.6 mmol) was added. The mixture was heated at reflux for 24 h, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with 1:4:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 1.0 g (85%) of the desired N-(3-phenoxyphenyl)-N-(4,4,4-trifluorobutyl)-3-(trifluoromethoxy)benzene-methanamine product as an off-white oil. ¹H NMR (CDCl₃) δ7.29 (m, 3H), 7.09 (m, 4H), 7.01 (s, 1H), 6.95 (d, 2H), 6.43 (d, 1H), 6.36 (d, 1H), 6.31 (s, 1H), 4.49 (s, 2H), 3.41 (t, 2H), 2.08 (m, 2H), 1.89 (q, 2H). ¹⁹F NMR (CDCl₃) δ−58.18 (s, 3F), −66.44 (t, 3F). Anal. calcd. for C₂₄H₂₁NO₂F₆: C, 61.41; H, 4.51; N, 2.98. Found: C, 61.16; H, 4.53, N, 2.92. HRMS calcd. 470.1555 [M+H]⁺, found: 470.1565.

EXAMPLE 1672

3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanthiol

EX-1672A) A solution of 3-(4-chloro-3-ethylphenoxy)aniline (3.72 g, 15 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (3.33 g, 15 mmol) is prepared in 60 mL of dichloroethane. Acetic acid (0.92 mL, 16.05 mmol) and solid NaBH(OAc)₃ (4.13 g, 19.5 mmol) are added. The mixture is stirred at room temperature for 3 hours, then is acidified with 1 N aqueous HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture is extracted with methylene chloride. The organic layer is washed with brine and water, then dried over anhydrous MgSO₄, and evaporated to give 5.00 g (85%) of the desired N-(3-(4-chloro-3-ethylphenoxy)phenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amine product.

Amine product EX-1672A (8 mmol) and 3,3,3-trifluoromethylthiirane (1.54 g, 12 mmol) are dissolved in 1.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.25 g, 0.4 mmol) is added, and the stirred solution is warmed to 50° C. under an atmosphere of nitrogen until completion of reaction as is indicated by HPLC analysis showing that no secondary amine starting material remains. The reaction is quenched with water and extracted with ether. The ether layer is washed with water and brine, then is dried over MgSO₄. The crude product is purified by flash column chromatography on silica gel with a solvent mixture to give the desired aminopropanethiol product.

EXAMPLE 1673

3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanamine

Amine product EX-1672A (8 mmol) and 3,3,3-trifluoromethylaziridine (1.33 g, 12 mmol) are dissolved in 1.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.25 g, 0.4 mmol) is added, and the stirred solution is warmed to 50° C. under an atmosphere of nitrogen until completion of reaction as is indicated by HPLC analysis showing that no secondary amine starting material remains. The reaction is quenched with water, the pH is adjusted to 9.5 with 2.5 N sodium hydroxide, and it is extracted with ether. The ether layer is washed with water and brine, then is dried over Na₂CO₃. The crude product is purified by flash column chromatography on silica gel with a solvent mixture to give the desired propanediamine product.

Bioassays

CETP Activity In Vitro

Assay of CETP Inhibition Using Purified Components (Reconstituted Buffer Assay)

The ability of compounds to inhibit CETP activity was assessed using an in vitro assay that measured the rate of transfer of radiolabeled cholesteryl ester ([³H]CE) from HDL donor particles to LDL acceptor particles. Details of the assay are provided by Glenn, K. C. et al. (Glenn and Melton, “Quantification of Cholesteryl Ester Transfer Protein (CETP): A) CETP Activity and B) Immunochemical Assay of CETP Protein.” Meth. Enzymol., 263, 339-351 (1996)). Human recombinant CETP can be obtained from the serum-free conditioned medium of CHO cells transfected with a cDNA for CETP and purified as described by Wang, S. et al. (J. Biol. Chem. 267, 17487-17490 (1992)). To measure CETP activity, [³H]CE-labeled-HDL, LDL, CETP and assay buffer (50 mM tris(hydroxymethyl)aminomethane, pH 7.4; 150 mM sodium chloride; 2 mM ethylenediamine-tetraacetic acid (EDTA); 1% bovine serum albumin) were incubated in a final volume of 200 μL, for 2 hours at 37° C. in 96 well plates. Inhibitors were included in the assay by diluting from a 10 mM DMSO stock solution into 16% (v/v) aqueous DMSO so that the final concentration of inhibitor was 800 μM. The inhibitors were then diluted 1:1 with CETP in assay buffer, and then 25 μL of that solution was mixed with 175 μL of lipoprotein pool for assay. Following incubation, LDL was differentially precipitated by the addition of 50 μL of 1% (w/v) dextran sulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes. A potion of the solution (200 μL) was transferred to a filter plate (Millipore). After filtration, the radioactivity present in the precipitated LDL was measured by liquid scintillation counting. Correction for non-specific transfer or precipitation was made by including samples that do not contain CETP. The rate of [³H]CE transfer using this assay was linear with respect to time and CETP concentration, up to 25-30% of [³H]CE transferred.

The potency of test compounds was determined by performing the above described assay in the presence of varying concentrations of the test compounds and determining the concentration required for 50% inhibition of transfer of [³H]CE from HDL to LDL. This value was defined as the IC₅₀. The IC₅₀ values determined from this assay are accurate when the IC₅₀ is greater than 10 nM. In the case where compounds have greater inhibitory potency, accurate measurements of IC₅₀ may be determined using longer incubation times (up to 18 hours) and lower final concentrations of CETP (<50 nM).

Examples of IC₅₀ values determined by these methods are specified in Table 9.

Assay of CETP Inhibition in Human Plasma

Blood was obtained from healthy volunteers, recruited from the personnel of Monsanto Company, Saint Louis, Mo. Blood was collected in tubes containing EDTA (EDTA plasma pool). The EDTA human plasma pool, previously stored at −20° C., was thawed at room temperature and centrifuged for 5 minutes to remove any particulate matter. Tritiated HDL, radiolabeled in the cholesteryl ester moiety ([³H]CE-HDL) as described by Morton and Zilversmit (J. Biol. Chem., 256, 11992-95 (1981)), was added to the plasma to a final concentration of 25 μg/mL cholesterol. Equal volumes (396 μL) of the plasma containing the [³H]CE-HDL were added by pipette into micro tubes (Titertube®, Bio-Rad laboratories, Hercules, Calif.). Inhibitor compounds, dissolved as 20-50 mM stock solutions in DMSO, were serially diluted in DMSO (or an alternative solvent in some cases, such as dimethylformamide or ethanol). Four μL of each of the serial dilutions of inhibitor compounds or DMSO alone were then added to each of the tubes containing plasma (396 μL). After mixing, triplicate aliquots (100 μL) from each plasma tube were then transferred to wells of 96-well round-bottomed polystyrene microtiter plates (Corning, Corning, N.Y.). Plates were sealed with plastic film and incubated at 37° C. for 4 hours. “Test” samples contained plasma with dilutions of inhibitor compounds. “Control” samples contained plasma with DMSO diluted to the same concentration as the test samples, but without inhibitor. “Blank” samples were prepared as “control” samples, but were left in the micro tubes at 4° C. for the 4 hour incubation and were then added to the microtiter wells at the end of the incubation period. VLDL and LDL were precipitated by the addition of 10 μL of precipitating reagent (1% (w/v) dextran sulfate (Dextralip50)/0.5 M magnesium chloride, pH 7.4) to all wells. The wells were mixed on a plate mixer and then incubated at ambient temperature for 10 min. The plates were then centrifuged at 1000×g for 30 min at 10° C. The supernatants (50 μL) from each well were then transferred to Picoplate™ 96 plate wells (Packard, Meriden, Conn.) containing Microscint™-40 (Packard, Meriden, Conn.). The plates were heat-sealed (TopSeal™-P, Packard, Meriden, Conn.) according to the manufacturer's directions and mixed for 30 min. Radioactivity was measured on a microplate scintillation counter (TopCount, Packard, Meriden, Conn.). The maximum percentage transfer in the control wells (% transfer) was determined using the following equation: ${\% \quad {Transfer}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{control}} \right\rbrack \times 100}{{dpm}_{blank}}$

The percentage of transfer relative to the control (% control) was determined in the wells containing inhibitor compounds was determined as follows: ${\% \quad {Control}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{test}} \right\rbrack \times 100}{{dpm}_{blank} - {dpm}_{control}}$

IC₅₀ values were then calculated from plots of % control versus concentration of inhibitor compound. IC₅₀ values were determined as the concentration of inhibitor compound inhibiting transfer of [³H]CE from the supernatant [³H]CE-HDL to the precipitated VLDL and LDL by 50% compared to the transfer obtained in the control wells.

Examples of IC₅₀ values determined by this method are specified in Table 10.

TABLE 9 Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. IC₅₀ Ex. IC₅₀ Ex. IC₅₀ No. (μM) No. (μM) No. (μM) 249 0.020 419 0.19 425 0.34 244 0.029 230 0.20 514 0.34 634 0.032 248 0.20 237 0.35 221 0.034 266 0.20 399 0.35 229 0.034 378 0.20 645 0.35 660 0.040 488 0.20 225 0.37 630 0.050 241 0.21 247 0.37 629 0.054 245 0.21 473 0.37 372 0.062 400 0.21 216 0.39 233 0.063 639 0.21 243 0.39 234 0.069 226 0.22 636 0.39 252 0.075 373 0.22 650 0.41 242 0.076 377 0.23 385 0.42 277 0.076 253 0.24 427 0.42 256 0.079 411 0.25 436 0.42 232 0.080 638 0.26 509 0.42 278 0.098 222 0.27 619 0.42 379 0.098 240 0.27 521 0.43 258 0.099 374 0.27 250 0.44 238 0.12 420 0.27 429 0.44 227 0.13 223 0.29 658 0.44 423 0.13 415 0.29 637 0.47 656 0.13 235 0.31 592 0.48 214 0.14 607 0.31 251 0.49 628 0.14 265 0.33 421 0.49 281 0.14 402 0.33 271 0.50 224 0.16 489 0.33 287 0.50 279 0.16 231 0.34 550 0.50 401 0.18 275 0.34 416 0.51 410 0.19 390 0.34 438 0.52 647 0.52 518 0.79 442 1.1 598 0.54 397 0.81 595 1.1 567 0.55 393 0.82 642 1.1 391 0.56 499 0.83 450B 1.1 559 0.56 648 0.83 71 1.2 246 0.57 282 0.84 305 1.2 268 0.58 396 0.86 381 1.2 527 0.58 581 0.87 441 1.2 269 0.59 294 0.88 446 1.2 292 0.59 557 0.88 492 1.2 405 0.60 218 0.91 496 1.2 409 0.61 601 0.91 524 1.2 475 0.64 653 0.91 569 1.2 254 0.65 422 0.92 693 1.2 450A 0.66 556 0.92 286 1.3 654 0.67 506 0.97 296 1.3 558 0.69 541 0.97 655B 1.3 389 0.70 274 0.99 264 1.4 412 0.71 651 0.99 392 1.4 408 0.75 77 1.0 406 1.4 554 0.75 267 1.0 522 1.4 280 0.76 293 1.0 526 1.4 525 0.76 439 1.0 568 1.4 578 0.76 560 1.0 582 1.4 440 0.77 657 1.0 74 1.5 523 0.77 659 1.0 79 1.5 646 0.77 599 1.0 403 1.5 166 0.78 285 1.1 407 1.5 424 0.78 395 1.1 444 1.5 593 0.78 398 1.1 495 1.5 456B 1.5 167 2.0 302 2.5 565 1.5 307 2.0 426 2.5 652 1.5 597 2.0 519 2.5 699 1.5 315 2.1 555 2.5 91 1.6 404 2.1 564 2.5 140 1.6 418 2.1 688 2.5 149 1.6 503 2.1 690 2.5 255 1.6 508 2.1 309 2.6 384 1.6 513 2.1 311 2.6 517 1.6 562 2.1 494 2.6 571 1.6 643 2.1 44 2.7 644 1.6 257 2.2 452 2.7 150 1.7 387 2.2 543 2.7 261 1.7 437 2.2 566 2.7 432 1.7 483 2.2 445 2.8 505 1.7 490 2.2 73 3.0 584 1.7 89 2.3 104 3.0 1670 1.8 299 2.3 115 3.0 212 1.8 318 2.3 220B 3.0 289 1.8 382 2.3 322 3.0 312 1.8 383 2.3 388 3.0 478 1.8 507 2.3 460 3.0 493 1.8 544 2.3 464 3.0 515 1.8 580 2.3 516 3.0 561 1.8 608 2.3 691 3.0 570 1.8 128 2.4 316 3.1 579 1.8 542 2.4 394 3.1 304 1.9 168 2.5 633 3.1 480 1.9 259 2.5 386 3.2 70 2.0 260 2.5 376 3.3 459 3.3 595B 4.5 310 6.6 317 3.4 701 4.5 514C 6.6 63 3.5 414 4.6 603 6.7 159 3.5 454 4.6 428 6.8 204 3.5 319 4.7 602 6.8 609 3.5 452 4.8 632 6.8 622 3.5 553 4.8 42 7.0 210 3.6 273 4.9 52 7.0 501 3.6 649 4.9 59 7.0 655 3.6 84 5.0 75 7.0 262 3.7 141 5.0 127 7.0 371 3.9 321 5.0 162 7.0 449 3.9 620 5.0 172 7.0 36 4.0 689 5.0 194 7.0 43 4.0 60 5.5 346 7.7 66 4.0 433 5.6 617 7.9 87 4.0 502 5.7 26 8.0 126 4.0 585 5.8 82 8.0 153 4.0 76 6.0 122 8.0 201 4.0 101 6.0 124 8.0 588 4.1 134 6.0 139 8.0 627 4.1 208 6.0 147 8.0 594 4.2 474 6.0 152 8.0 606 4.2 239 6.1 453 8.0 448 4.3 512 6.1 290 8.1 640 4.3 591 6.2 625 8.3 297 4.4 576 6.4 291 8.4 491 4.4 583 6.4 90 9.0 209 4.5 434B 6.4 112 9.0 375 4.5 270 6.5 129 9.0 323 9.0 136 12 67 15 215 9.2 158 12 68 15 456 9.2 288 12 98 15 621 9.3 431 12 145 15 447 9.8 462 12 148 15 25 10 466 12 185 15 47 10 605 12 186 15 72 10 611 12 198 15 78 10 687 12 200 15 131 10 38 13 308 15 146 10 451 13 347 15 163 10 457 13 589 15 193 10 458 13 661 15 199 10 461 13 686 15 236 10 463 13 694 15 486 10 596 13 695 15 551 10 211 14 514D 15 572 10 314 14 35 16 613 10 504 14 692 16 213 11 590 14 612A 16 301 11 19 15 276 17 380 11 23 15 295 17 472 11 39 15 413 17 477 11 50 15 417 17 641 11 53 15 1669 17 528B 11 54 15 62 18 1671 11 57 15 197 18 31 12 58 15 220 18 41 12 64 15 574 18 92 12 33 15 616 18 51 20 106 30 17 45 55 20 138 30 118 45 56 20 195 30 345 45 65 20 520 30 362 45 69 20 626 30 604 46 80 20 300 31 529 49 83 20 217 32 22 50 86 20 320 32 34 50 113 20 303 33 93 50 135 20 103 35 96 50 137 20 105 35 120 50 160 20 348 35 350 50 173 20 352 35 351 50 313 20 468 35 471 50 324 20 612 35 662 50 610 20 702 35 697 55 683 20 1 38 3 60 30 22 94 40 4 60 455 22 114 40 14 60 61 23 116 40 16 60 192 23 142 40 18- 60 587 23 156 40 95 60 298 24 196 40 102 60 620A 24.6 335 40 108 60 109 25 357 40 110 60 117 25 363 40 203 60 125 25 497 42 685 60 132 25 473B 42 111 65 133 25 528C 42 119 70 306 25 528 43 342 70 353 70 435 >50 263 >50 664 70 435B >50 284 >50 28 75 443 >50 430 >50 88 75 465 >50 434 >50 107 75 467 >50 563 >50 355 75 469 >50 573 >50 85 80 470 >50 575 >50 130 80 476 >50 577 >50 143 80 479 >50 586 >50 332 80 484 >50 632A >50 366 80 487 >50 5 >100 635 80 498 >50 6 >100 665 80 500 >50 7 >100 97 90 511 >50 8 >100 100 90 530 >50 9 >100 123 90 531 >50 10 >100 165 90 532 >50 11 >100 207 90 533 >50 12 >100 2 100 534 >50 13 >100 45 100 535 >50 15 >100 144 100 536 >50 20 >100 333 100 537 >50 21 >100 334 100 538 >50 24 >100 340 100 539 >50 27 >100 343 100 540 >50 29 >100 618 100 545 >50 32 >100 663 100 546 >50 37 >100 672 100 547 >50 40 >100 696 100 548 >50 46 >100 698 100 549 >50 48 >100 49 >100 325 >100 588B >100 81 >100 326 >100 614 >100 99 >100 327 >100 615 >100 121 >100 328 >100 631 >100 161 >100 329 >100 634C >100 164 >100 330 >100 667 >100 16g >100 331 >100 668 >100 170 >100 336 >100 669 >100 171 >100 337 >100 670 >100 174 >100 338 >100 671 >100 175 >100 339 >100 673 >100 176 >100 341 >100 674 >100 177 >100 344 >100 675 >100 178 >100 349 >100 676 >100 179 >100 354 >100 677 >100 180 >100 356 >100 678 >100 181 >100 358 >100 679 >100 182 >100 359 >100 680 >100 183 >100 360 >100 681 >100 184 >100 361 >100 682 >100 187 >100 364 >100 684 >100 188 >100 365 >100 189 >100 367 >100 190 >100 368 >100 191 >100 369 >100 202 >100 370 >100 205 >100 151 >100 206 >100 154 >100 219 >100 155 >100 283 >100 157 >100

TABLE 10 Inhibition of CETP Activity by Examples in Human Plasma Assay. Ex. IC₅₀ Ex. IC₅₀ Ex. IC₅₀ No. (μM) No. (μM) No. (μM) 229 0.56 256 7.8 554 18 221 0.88 559 8.0 266 21 233 1.0 637 8.0 645 21 234 1.0 245 8.4 269 22 660 1.1 489 8.8 287 22 630 1.8 450A 9.0 280 23 249 2.3 265 9.6 216 24 402 2.9 240 9.7 377 24 242 3.1 248 10 390 24 399 3.4 275 10 440 24 232 3.4 395 10 657 24 629 3.4 396 10 391 25 244 3.8 397 10 251 26 252 3.9 281 11 253 27 634 4.1 560 11 267 27 401 4.2 638 11 385 29 488 4.3 241 12 438 29 429 4.4 282 12 166 30 619 4.9 373 12 294 30 393 5.0 378 12 550 30 639 5.0 654 12 650 30 258 5.2 246 13 658 30 214 5.7 278 13 218 31 628 5.7 439 13 250 31 372 5.7 647 13 243 34 405 6.2 436 14 271 34 400 6.3 279 15 499 34 277 6.5 274 16 557 34 656 6.9 473 16 128 35 379 7.7 247 17 71 36 268 37 42 80 299 >100 475 37 140 80 302 >100 292 38 150 80 309 >100 558 38 307 81 311 >100 653 38 601 83 315 >100 374 39 296 86 316 >100 77 40 59 100 317 >100 293 42 73 100 321 >100 595 42 43 110 322 >100 126 45 201 110 346 >100 74 48 60 120 600 >100 655 48 63 120 649 >100 556 49 66 120 686 >100 593 49 75 200 688 >100 642 50 389 >50 691 >100 592 52 447 >50 220B >100 699 55 104 >100 595B >100 79 60 115 >100 35 >200 87 60 127 >100 36 >200 89 60 131 >100 76 >200 655B 63 141 >100 661 >200 70 65 149 >100 664 >200 312 65 168 >100 33 500 659 65 204 >100 84 70 208 >100 91 70 209 >100 690 75 210 >100 304 76 219 >100 305 76 273 >100 254 77 297 >100 

What is claimed is:
 1. A method of treating or preventing a CETP-mediated disorder in a subject by administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, said compound being of Formula I:

wherein; X is selected from the group consisting of O, S, NH and N(alkyl); Y is a bond or (C(R₁₄)₂)_(q) wherein q is 1 or 2; Z is a bond or (C(R₁₅)₂)_(q) wherein q is 1 or 2; R₁₄ and R₁₅ are independently hydrido or alkyl; R₁₆ is bonded together with R₁₄ or R₁₅ to form a heterocyclyl ring having from 5 through 10 members, with the proviso that Y is (C(R₁₄)₂)_(q) or that Z is (C(R₁₅)₂)_(q); n is 1 or 2; R₁ is haloalkoxyalkyl or haloalkyl with the proviso that said haloalkyl has two or more halo substituents; R₂ is selected from the group consisting of hydrido, hydroxyalkyl, aminoalkyl, aryl, aralkyl, alkyl, alkenyl, alkynyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, and heteroaralkyl; R₃ is selected from the group consisting of hydrido, alkyl, alkenyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, and cycloalkenylalkyl; R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido or with the proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 2. The method of claim 1, wherein said compound is of Formula I, wherein at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 3. The method of claim 2, wherein said compound is of Formula I, wherein; X is selected from the group consisting of O, S, and NH; Y is a bond or CH(R₁₄); Z is a bond or CH(R₁₅); one of R₁₄ and R₁₅ is hydrido or alkyl; R₁₆ is bonded together with R₁₄ or R₁₅ to form a heterocyclyl ring having from 5 through 8 members, with the proviso that Y is CH(R₁₄) or that Z is CH(R₁₅); n is 1 or 2; R₁ is haloalkoxyalkyl or haloalkyl with the proviso that said haloalkyl is selected from other than monohaloalkyl; R₂ is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, and aminoalkyl; R₃ is hydrido; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylamino, alkylthio, arylamino, arylthio, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 4. The method of claim 3, wherein said compound is of Formula I, wherein; X is O or S; Y is a bond or CH(R₁₄); Z is a bond or CH(R₁₅); one of R₁₄ and R₁₅ is hydrido or methyl; R₁₆ is bonded together with R₁₄ or R₁₅ to form a heterocyclyl ring having 5 or 6 members, with the proviso that Y is CH(R₁₄) or that Z is CH(R₁₅); n is 1; R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is selected from the group consisting of hydrido, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methyl, aminomethyl, 1-aminoethyl, and 2-aminoethyl; R₃ is hydrido; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R ₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 5. The method of claim 4, wherein said compound is of Formula I, wherein; X is O; Y is CH(R₁₄); Z is a bond; R₁₆ is bonded together with R₁₄ to form a 5-membered heterocyclyl; n is 1; R₁ is selected from the group consisting of trifluoromethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido or hydroxymethyl; R₃ is hydrido; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylamninophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 6. The method of claim 3, wherein said compound is of Formula II:

wherein; X is O or S; R₁ is haloalkoxyalkyl or haloalkyl with the proviso that said haloalkyl has two or more halo substituents; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylthio, arylamino, arylthio, arylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 7. The method of claim 6, wherein said compound is of Formula II, wherein; X is O or S; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl, 1,1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio; R₆, R₇, R₁₁, and R₁₂ are independently hydrido or fluoro.
 8. The method of claim 7, wherein said compound is of Formula II, wherein; X is O; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of 1,1,2,2-tetrafluoroethoxy, pentafluoroethyl, and trifluoromethyl; R₆, R₇, R₁₁, and R₁₂ are independently hydrido or fluoro.
 9. The method of claim 1, wherein said compound is:


10. The method of claim 1 further characterized by treating coronary artery disease in a subject by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 11. The method of claim 1 further characterized by preventing coronary artery disease in a subject by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 12. The method of claim 1 further characterized by preventing cerebral vascular accident (CVA) in a subject by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 13. The method of claim 1 further characterized by treating or preventing dyslipidemia in a subject by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 